The Cancer Problem

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION ChapterNOT 1 FOR SALE OR DISTRIBUTION Biology of Cancer Chapter 2 © Jones & Bartlett Learning,Immunology LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONChapter 3 NOT FOR SALE OR DISTRIBUTION Epidemiology

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CHAPTER

Julia A. Eggert, PhD, RN, AGN-BC, AOCN®, FAAN © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORBiology SALE OR DISTRIBUTION of Cancer NOT FOR SALE OR DISTRIBUTION

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION ➣➣ Introduction Enabler: Immune Response Cells ➣➣ Models and Theory of Cancer Enabler: Signaling Molecules Development ➣➣ Hallmark: Deregulated Growth © Jones &Clonal Bartlett Model Learning, LLC © Jonesand & Mi Bartletttogenesis Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Cancer Stem Cell Model ➣➣ Hallmark: Metabolic Programming Plasticity Model of Cancer Stem Cells ➣➣ Hallmark: Suppression of Apoptosis Inflammation Theory Driver: Decreased Cell Attrition ➣➣ Hallmarks, Drivers, and Enablers Role of Potassium, Sodium, and Calcium Ions of Cancer © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION➣➣ Hallmark: Evasion of SenescenceNOT FOR SALE OR DISTRIBUTION ➣➣ Hallmark: Genetic Instability Oncogenes and Tumor Suppressor Genes Definitions of Individual DNA Noncoding RNAs Categories of Genes Associated With Cancer MicroRNAs Sources of Cancer-Causing Changes in DNA ➣➣ Hallmark: Evasion of Immunity Passenger© Jones and & DriverBartlett Mutations Learning, LLC © Jones & Bartlett Learning, LLC TypesNOT of DNAFOR RepairSALE OR DISTRIBUTION ➣➣ Hallmark:NOT Disruption FOR SALE of Epithelial OR DISTRIBUTION Epigenetic Mechanisms Adhesion and Polarity Enabler: Loss of Heterogeneity Driver: Activating Invasion and Metastasis Driver: Cancer Susceptibility Genes Altered Surface Charge Density ➣ © Jones➣ &➣ Hallmark: Bartlett Learning, Defective DNALLC Repair and © Jones➣ Hallmark: & Bartlett Matrix Learning, Degradation LLC and Gain NOT FOR MaintenanceSALE OR DISTRIBUTION NOT FORin Moti SALElity OR DISTRIBUTION Enabler: Inducing Inflammation ➣➣ Signaling Networks and Circuitry Enabler: Inducing Angiogenesis Motility Circuits ➣➣ Hallmark: Microenvironment Cytostasis and Differentiation Circuits Enabler: Cancer Stem© Jones Cells & Bartlett Learning, LLCProliferation Circuits © Jones & Bartlett Learning, LLC Enabler: Epithelial–MesenchymalNOT FOR SALE Transition OR DISTRIBUTIONViability Circuits NOT FOR SALE OR DISTRIBUTION Cancer Stem Cell Plasticity ➣➣ Conclusion Driver: Telomerase ➣➣ References © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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4 PART I The Cancer Problem

INTRODUCTION multistep tumorigenesis, heritable genetic and epigenetic © Jones & Bartlett Learning, LLC © Joneschanges & Bartlett accumulate Learning, to an ever LLC greater extent, encourag- NOT FORResearch SALE into OR the DISTRIBUTION biology of the cancer cell has led to betterNOT FORing transformation SALE OR DISTRIBUTION of normal cells into a lineage of malig- understanding of the signaling pathways and the molecular nant cells. The accumulation of multiple genetic mutations machinery that drives the ability of cancer cells to prolifer- confers beneficial traits that further alter the heterogeneity ate, resist attrition, and invade surrounding and long dis- of cells, supporting clonal expansion. Because the genetic tance tissues. As the altered machinery of the cancer cell variants accumulate more malignant characteristics that becomes more defined,© Jonesbetter targeted & Bartlett therapies Learning, may be LLCbenefit their growth, these© Jonescells proliferate & Bartlett more Learning,rapidly at LLC developed.1 It is importantNOT that FOR nurses SALE in the OR various DISTRIBUTION oncol- the expense of the less fitNOT clones. FOR Consequently, SALE OR examinaDISTRIBUTION- ogy settings have the understanding and ability to translate tion of the late-stage tumor reveals much heterogeneity in 5 this molecular information into their patient care. its makeup. The double helix was identified in the 1950s. Emerging genetics© knowledgeJones & wasBartlett not included Learning, in high LLC school biology © Jones & Bartlett Learning, LLC CANCER STEM CELL MODEL textbooksNOT until FOR the SALElate 1970s. OR The DISTRIBUTION average age of the newly NOT FOR SALE OR DISTRIBUTION diagnosed patient is 66, born in 1949. Most of these new patients had a limited education in biology, cellular biol- The focus of the second model is the mutationally corrupt ogy, and certainly genetics. In addition, most of the current heterogeneous cancer stem cell. In this model, cancer cells oncology nurses are in their late 40s and early 50s, creating show a hierarchy of development, such that a few stem cells © Jonesa & similar Bartlett lack ofLearning, molecular LLCknowledge, especially in regard© Jones have & the Bartlett ability toLearning, produce progeny, LLC but demonstrate lim- 6 NOT FORto SALEgenetics. OR2 Oncology DISTRIBUTION nurses today need to embrace NOTthe FORited proliferation SALE OR potential. DISTRIBUTION As the cells divide and prolifer- challenge to understand the complexity of the biology of ate, only one subpopulation has the capability of becoming malignant cells, know how to translate this new and robust tumorigenic, with the consequent ability to drive growth knowledge into cancer care, and be able to simply explain and expansion of the malignancy. The successful survival and proliferation of these CSCs depends on their ability this multifaceted information© Jones to &their Bartlett patients Learning, and fami- LLC © Jones & Bartlett Learning, LLC 3 to undergo self-renewing mitotic divisions where at least lies. The goal of this NOTchapter FOR is to SALEprovide ORsimple DISTRIBUTION descrip- NOT FOR SALE OR DISTRIBUTION tions of complex concepts for those nurses new to oncology, one of the progeny maintains its ability to multiply, virtu- whether they are looking for a new challenge or just begin- ally forever. Ultimately, this subpopulation of cells within a ning their careers in cancer nursing. tumor is responsible for the growth and progression of the malignancy.4 © Jones & Bartlett Learning, LLC Three© Jonesclasses of& connectiveBartlett Learning, tissue support LLC the CSC MODELSNOT ANDFOR THEORYSALE OR OF DISTRIBUTION CANCER functionNOT in a varietyFOR SALEof tumor OR types. DISTRIBUTION The first class, con- DEVELOPMENT sisting of the endothelial cells, pericytes, and perivascular cells, organizes CSCs in the microenvironment into vas- The pathology of cancer demonstrates various phenotypes cular niches within the primary tumors and metastatic due to heterogeneity created from diverse cell types plus sites.7–9 Cancer-associated fibroblasts (CAFs) constitute the © Jonesgenetic & Bartlett or epigenetic Learning, differences LLC among the cancer cells;© put Jones second & Bartlett class of connectiveLearning, tissue LLC induced by cancer cells. NOT FORsimply, SALE each OR cancer DISTRIBUTION is different.4 There are two commonlyNOT FORThese SALE CAFs ORswitch DISTRIBUTION to an unusual aerobic form of glycoly- recognized models of cancer development: clonal evolution sis, secreting lactate (along with the tumor cells) plus pyru- and development of the cancer stem cell (CSC). Both mod- vate to be used as energy to fuel cancer cell proliferation.4,6 els suggest a path to metastatic disease. A third model of Finally, the third class includes the columnar cells important for water absorption. tumorigenicity proposes© thatJones plasticity & Bartlett exists between Learning, the LLC © Jones & Bartlett Learning, LLC non-CSCs and CSC compartments such that non-CSCs As the new tumor is established, the growing hetero- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION can reacquire a CSC phenotype. The theory of inflam- geneous populations cause progressive enlargement of mation suggests the association of inflammation with the the tumor while the CSCs move into the resting phase of development of cancer. It addresses the many populations the cycle (G0). Cells in this phase of the cell cycle remain and subpopulations of immune cells in and around the sequestered and are known to be resistant to cancer treat- tumor© that Jones seem &to Bartlett have an unsubstantiatedLearning, LLC rationale for ment. The© Jonesother non-CSCs & Bartlett remain Learning, in the chronically LLC divid- their presenceNOT FOR other SALE than sustaining OR DISTRIBUTION the malignant process. ing phasesNOT of theFOR cell SALE cycle (G OR1, S, DISTRIBUTION G2, and M), in which they proliferate. Because they are dividing rapidly, they can be destroyed by a variety of treatments or the inherent CLONAL MODEL immune system. Years later, the “resting” CSC can move back into the active phases of the cell cycle (G , S, G , © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 1 2 The clonal model suggests that initial damage to the and M). They do not slip out of the cycle into the G0 rest- NOT FORDNA SALE results OR in DISTRIBUTIONbenign tumor growth.4 Over time, duringNOT FORing phase, SALE however; OR DISTRIBUTION consequently, there may be continuous

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CHAPTER 1 Biology of Cancer 5

proliferation and exacerbation of a cancer that was believed growth and development; however, there are known hall- 4,10,11 © Jonesto be &in remissionBartlett orLearning, cured. LLC © Jonesmarks of& Bartlettcancer that Learning, are associated LLC with the aberrant NOT FOR SALE OR DISTRIBUTION NOTchanges. FOR InSALE addition, OR otherDISTRIBUTION functions have been identified that drive and foster tumorigenesis.14 PLASTICITY MODEL OF CANCER STEM CELLS The functions of the cell that drive cancer development are increased proliferation, decreased attrition, and inva- A newer model embraces the CSC theory, but suggests sion of tissue. The acquired hallmarks of cancer include there is plasticity between the© Jonesnon-CSCs & withBartlett low potential Learning, core LLC changes to the cell such as© theJones ability & to Bartlett sustain prolif Learning,- LLC to become tumors and the CSCsNOT withFOR tumorigenic SALE OR capabil DISTRIBUTION- erative signaling, evasion of growthNOT FORsuppressors, SALE replicative OR DISTRIBUTION ity. The CSC model suggests these cells move in a one-way immortality, resistance of cell death, deregulation of defec- fashion through division to either replenish the CSC pool tive DNA repair, angiogenesis, and evasion of immunity. or become non-CSCs with very low tumorigenic potential. Genetic instability, inflammation, angiogenesis, and fibro- New research© Jones indicates & thatBartlett some carcinomasLearning, may LLC be able sis foster the ©malignant Jones transformation.& Bartlett Learning, The changes LLC asso- to convert their non-CSCs into aggressive de novo CSCs, ciated with these elements provide an organizing structure NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION in a bidirectional conversion.4 to better understand the dysregulation of the cell associated with malignant transformation. These malignant changes vary with the type of cancer and the organ affected.15,16 INFLAMMATION THEORY Hallmarks are the traits or characteristics of tumor © Jones & Bartlett Learning, LLC © Jonescells that & sustainBartlett oncogenic Learning, tasks. LLC The instability of the NOT TheFOR inflammation SALE OR DISTRIBUTION theory of cancer development proposes NOTgenome, FOR inflammation,SALE OR DISTRIBUTION angiogenesis, and fibrosis enable that a variety of infectious agents and their relationships tumor progression by fostering maintenance of gene muta- with inflammatory cells plus chronic inflammation are tions through defective DNA repair, recruitment of normal the primary cause of cancer, including the proliferation, cells while molding the tumor, and alterations made to the survival, and ultimate migration of cancer cells. This the- microenvironment.1,16,17 ory also stresses the inclusion© Jones of factors & Bartlett from the Learning,innate LLC © Jones & Bartlett Learning, LLC immune system, includingNOT selectins, FOR chemokines SALE OR (such DISTRIBUTION as NOT FOR SALE OR DISTRIBUTION NF-kappa-B), and their receptors, that have the ability to HALLMARK: GENETIC INSTABILITY encourage invasion, migration and metastasis.12,13 Vogelstein18 was the first to note that “all cancer is genetic.” © Jones & Bartlett Learning, LLC This statement© Jonesis based &on Bartlett the central Learning, dogma that LLC DNA is HALLMARKS,NOT FOR DRIVERS, SALE AND OR DISTRIBUTIONENABLERS transcribed intoNOT RNA, FOR and SALE all RNA OR is DISTRIBUTIONtranslated into pro- OF CANCER tein, even in a malignancy. This dogma persists even though matters have become more complicated over time with the The microenvironment associated with the various models inclusion of more types of RNA (Table 1-1).19–24 Research of cancer development plays an important role in malignant into malignancies has revealed much about defective DNA © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT TABLEFOR SALE 1-1 OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Types and Functionality of RNA

RNA Function © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Messenger RNA (mRNA)20 NOT FOR SALEOrders ORnucleotides DISTRIBUTION into amino acids for protein expressionNOT FOR SALE OR DISTRIBUTION Ribosomal RNA (rRNA)20 Provides structural support for the protein Transfer RNA (tRNA)20 Brings amino acids to site of protein synthesis MicroRNA (miRNA)21,22 Short noncoding RNA that inhibits mRNA so there is decreased gene expression Piwi-interacting© Jones RNA & Bartlett Learning,Epigenetic LLC and post-transcriptional gene© thatJones silences & Bartlettgermline cells, Learning, especially LLC (piRNA)21,23NOT FOR SALE OR DISTRIBUTIONspermatogenesis NOT FOR SALE OR DISTRIBUTION Small interfering RNA Gene silencing (siRNA)21,24 Short hairpin RNA Short sequence of RNA that makes a tight hairpin turn to be used to silence targeted 24 © Jones(shRNA) & Bartlett Learning, LLC gene expression; usually© Jones delivered & via Bartlett plasmid or Learning, bacterial vectors LLC NOT Source:FOR Data SALE from GhildiyalOR DISTRIBUTION and Zamore20; Ritchier et al21; Siomi et al22; WhiteheadNOT FOR et al23 SALE; Wang et al. OR24 DISTRIBUTION

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6 PART I The Cancer Problem

repair and genetic instability and how these processes are the ride.”30,31 Different cancers may have a variable mixture © Jonesassociated & Bartlett with Learning, the biology LLCof cancer. © Jonesof driver & Bartlett and passenger Learning, mutations, LLC yet still demonstrate the NOT FOR SALE OR DISTRIBUTION NOT FORpresence SALE of similar OR DISTRIBUTION phenotypes. The drivers in this combination of mutated gene sets can be targeted for treatment, DEFINITIONS OF INDIVIDUAL DNA either individually or in a staggered approach.30–32

Most DNA (99.9%) is the same among individuals. A change in the DNA or RNA that© Jonesoccurs in & a populationBartlett Learning, and is asso- LLCTYPES OF DNA REPAIR© Jones & Bartlett Learning, LLC ciated with normal variationNOT isFOR identified SALE as ORa polymorphism DISTRIBUTION NOT FOR SALE OR DISTRIBUTION (0.1%).10 Disease-causing changes to DNA are identified as Most normal cells have driver and passenger mutations that mutations. Such disease-causing mutations can occur in the could be restored to their pre-damage levels through the germline (inherited DNA originally from the egg and sperm normal DNA repair mechanisms; this is obviously impor- or gametes)© Jones or in the& Bartlettsomatic cells Learning, (DNA found LLC in every cell tant for ©cancer-free Jones &survival. Bartlett These Learning, DNA repair LLC systems of the body except the sperm and the egg).25,26 include (1) the nucleotide repair (NER) groups, which NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION address mutations associated with xeroderma pigmento- sum; (2) the mismatch repair (MMR) genes, which accom- CATEGORIES OF GENES ASSOCIATED WITH pany the inherited predisposition to colorectal cancer CANCER (CRC); (3) DNA crosslink repair (Fanconi anemia genes); © Jones & Bartlett Learning, LLC © Jonesand & (4) Bartlett the well-known Learning, DNA LLC repair genes exemplified by NOT FORMutations SALE ORcan occur DISTRIBUTION in normal genes that direct cell growthNOT FORthe breast SALE cancer OR genesDISTRIBUTION (BRCA1/2). To date, approximately (proto-oncogenes), such as ras or v-src, enabling them to 130 genes have been linked to DNA repair.33 be activated into cancer-causing genes (oncogenes), which have the trait of ongoing cell proliferation.27 Mutations can also occur in tumor suppressor genes,28 including p53, EPIGENETIC MECHANISMS Rb, WT1, BRCA1, BRCA2© Jones, VHL ,& APC Bartlett, NF-1 ,Learning, NF-2, and LLC © Jones & Bartlett Learning, LLC MTS-1. When readingNOT the literature,FOR SALE genes OR are DISTRIBUTION typically Epigenetic mechanisms canNOT affect FOR the SALE DNA ORrepair DISTRIBUTION genes. identified byitalics (p53), while the proteins of the genes While the changes noted previously affect the primary are not italicized (p53). DNA sequence of the repair systems, epigenetic changes occur “above and over” the DNA; consequently, they do © Jones & Bartlett Learning, LLC not affect© Jonesthe basic & structure, Bartlett butLearning, rather have LLC the capac- SOURCESNOT OF FOR CANCER-CAUSING SALE OR DISTRIBUTION CHANGES IN DNA ity to determineNOT FOR when SALE and where OR genes DISTRIBUTION might be expressed (turned on) by altering the chromatin.34,35 Normal cell processes cannot continue when a disease- Chromatin is the material within a chromosome that causing mutation is present. Programmed cell death (apop- consists of protein and DNA.36 The major proteins of chro- tosis) will not occur if tumor suppressor genes damage the matin are the histones, which are responsible for compact- © Jonescell & Bartlettso that it becomes Learning, immortalized. LLC As mutations accumu© -Jonesing &the Bartlett primary DNALearning, by wrapping LLC it tightly (like thread on NOT FORlate SALE in these OR two DISTRIBUTION types of regulatory genes, proliferation alsoNOT FORa spool) SALE so it ORfits DISTRIBUTIONwithin the nucleus of the cell. These con- increases; thus immortalization of the cells works together tinuous strands of DNA and histones appear like “beads with this process to allow development of a malignancy. on a string” (euchromatin). When multiple histones wrap Other types of cancer-causing changes in genes include tightly together (heterochromatin), they prevent transcrip- point mutations, deletions, duplications, insertions, trans- tion and contain inactive genes.35–37 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC locations, chromosomal aberrations, incorporation of viral Both the DNA and the histone proteins may become segments of genetic material,NOT FORand epigenetic SALE OR inactivation. DISTRIBUTION29 modified with additionNOT or removal FOR SALEof chemical OR DISTRIBUTION groups, the core of epigenetics. Methyl groups can be added to or removed from DNA, while phosphate, acetyl, or ubiquitin PASSENGER AND DRIVER MUTATIONS groups can be added to or removed from the histones. Most © Jones & Bartlett Learning, LLC commonly,© Jones methyl groups& Bartlett are added Learning, to the core LLC DNA and 35,37,38 The NOTcurrent FOR literature SALE describes OR DISTRIBUTION both passenger and driver acetyl groupsNOT to FOR the histones. SALE OR DISTRIBUTION mutations. Driver mutations (e.g., TP53) are directly asso- The nucleosome is a composition of eight separate his- ciated with oncogenesis and are selected in the microen- tone molecules, with two loops of DNA wrapped around vironment of the cancer for clonal advantage. Passenger each group of eight histones.35,37 Because histones are pro- mutations are found in the same tumors but do not offer teins, they can be modified after translation by attachment © Jonesany & Bartlettclonal advantage Learning, and do LLC not contribute to the develop© -Jonesof acetyl, & Bartlett phosphate, Learning, or ubiquitin LLC groups to their “tails.”39 NOT FORment SALE of the OR cancer DISTRIBUTION type; thus they are viewed as “along NOTfor FOREpigenetic SALE readers OR DISTRIBUTION are types of enzymes that promote

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CHAPTER 1 Biology of Cancer 7

addition and release of methyl, acetyl, and lysine methyl when mutated, are closely associated with the development 44–46 © Joneschemical & Bartlett groups to Learning,the “tail”; they LLC are used in transcription. © Jonesand progressions & Bartlett of human Learning, cancers. LLC NOT NoFOR chemical SALE group OR additionsDISTRIBUTION will close the histones, so no NOT FOR SALE OR DISTRIBUTION epigenetic reading occurs with tightly packed histones that might prevent DNA expression. Instead, attachment of the DRIVER: CANCER SUSCEPTIBILITY GENES chemical groups to the tail causes loose packing, which promotes epigenetic reading and DNA expression with Probably the best-known cancer susceptibility gene is the protein growth. The chemical© Jones groups & causeBartlett changes Learning, that tumor LLC suppressor gene TP53© (located Jones on& Bartlett17p13), which Learning, LLC alter the shape of the chromatinNOT FORin specific SALE places OR DISTRIBUTIONon the commonly has mutations, frequentlyNOT FOR involving SALE deletions OR DISTRIBUTION of genome, making some areas more available to gene expres- genomic material. This gene is associated with a wide vari- sion. These types of epigenetic modifications are now being ety of cancer types, including lung, breast, esophageal, liver, explored as targets of cancer therapy for malignancies such and bladder cancer; ovarian carcinoma; brain tumor; and as chronic ©myelogenous Jones & Bartlettleukemia (CML),Learning, gastrointestinal LLC malignancies© of Jones the immune & Bartlett and hematopoietic Learning, systems.LLC (GI) stromal tumors, and breast cancer.40 Such epigenetic Because it contributes to the signaling circuitry between NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION changes can be reversed, but there is also a possibility that genes, TP53 is designated “champion of the genome” and they may be transmitted to daughter cells.40,41 is believed to be involved in approximately 50% of sporadic A frequent finding with cancer is methyl groups added human cancers; thus TP53 is the most common genetic to the DNA, where clusters of guanine (G) follow cytosine target for mutations leading to cancers. When inherited as a © Jones(C); these& Bartlett so-called Learning, CpG islands LLC cause gene expression to © Jonesgermline & mutation, Bartlett it Learning, is transmitted LLC in an autosomal domi- NOT beFOR suppressed. SALE Normally,OR DISTRIBUTION the CpG islands occur in areas of NOTnant FOR fashion, SALE a hallmark OR DISTRIBUTION of hereditary cancer syndromes.45 the DNA where gene expression is initiated (promoter). In Phosphatase and tensin homolog (PTEN) is part of a healthy cells, they are mostly unmethylated, allowing tumor family of genes collectively called the protein tyrosine phos- suppressor genes and proto-oncogenes to be expressed nor- phatases (PTP). PTEN produces a ubiquitous protein that mally, and permitting apoptosis and controlled limited cell acts as a tumor suppressor to help regulate cell-cycle divi- proliferation to take place.37,40-42© Jones & Bartlett Learning,sion: LLC It issues a “stop” order to© prevent Jones progression & Bartlett through Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Mutations in oncogenes and tumor suppressor genes G1 and trigger the cell to begin the process of apoptosis. coexist in the development of a cancer.3 The phenotypes Research suggests the protein also participates in migra- associated with these mutations vary among many types of tion, adhesion, and angiogenesis, in addition to playing cancer.43 In colon cancer, for example, each person’s tumor a role in stabilizing the genome.47,48 The PTEN enzyme is as distinctive© Jones as a snowflake, & Bartlett with Learning, a unique set LLC of mutated antagonizes ©the Jones PI3K signaling& Bartlett pathway Learning, and negatively LLC genes accumulatingNOT FOR in anSALE unpredictable OR DISTRIBUTION order, both drivers regulates theNOT mitogen-activated FOR SALE proteinOR DISTRIBUTION kinase (MAPK) and passengers.3 Somatic mutations found in some human pathway, thereby placing constraints on cell propagation.49 tumors are reviewed in Table 1-2.2,39–41 The PI3K/AKT/mTOR pathway comprises an intracellular circuitry that performs an important function by carrying signals to the nucleus to ensure regulation of the cell cycle. © JonesENABLER: & Bartlett LOSS OF Learning, HETEROZYGOSITY LLC © JonesPhosphatidylinositol-3-OH & Bartlett Learning, kinase LLC (PI3K) activates phos- NOT FOR SALE OR DISTRIBUTION NOTphorylation FOR SALE to nudge OR AKT DISTRIBUTION and localize it on the cell mem- When both alleles are identical, they are referred to as brane.50 When cell glucose is elevated in the normal cell, homozygous. If one of the alleles has an inherited mutation such that plentiful energy is available for metabolism, the of a tumor suppressor gene (with loss of genetic material), cell will be more likely to proliferate; conversely, less glucose it is termed heterozygous because the alleles are different. availability causes quiescence due to the p21 tumor sup- © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Because there is a normal allele, the function of the gene pressor protein.51 The AKT signal has many effects, includ- and its protein product is NOTmaintained. FOR SALEOnce the OR remain DISTRIBUTION- ing activation of mTOR; mTORNOT (mechanisticFOR SALE target OR DISTRIBUTIONof ing allele is mutated, however, the gene and its product rapamycin) promotes expression of the protein kinase that (protein) will lose normal functioning. This further altera- regulates cell growth, cell proliferation, cell motility and tion and loss of genetic material is labeled loss of heterozygos- survival, protein synthesis, and transcription.52 When asso- ity (LOH).© The Jones loss of& an Bartlett entire chromosome, Learning, translocation LLC ciated with a© malignancy, Jones & theBartlett PI3K/AKT/mTOR Learning, pathwayLLC of a piece NOTof the FOR chromosome, SALE ORreduplication DISTRIBUTION of a piece of is hyperactive,NOT enabling FOR cellular SALE proliferation OR DISTRIBUTION and decreas- chromosome that already has an abnormal gene, or devel- ing apoptosis. Mutations in genes or in proteins expressed opment of a point mutation in the second functioning allele by genes are associated with this important signaling path- is included in the LOH definition. way and have been the target of multiple therapies.53 Cancer susceptibility genes such as oncogenes and tumor The epidermal growth factor receptor gene EGFR( ) © Jonessuppressor & Bartlett genes can Learning, develop LOH. LLC Basic research is identi- © Jonesis a tumor & Bartlett suppressor Learning, gene. This LLC gene expresses a trans- NOT fyingFOR an SALE increasing OR numberDISTRIBUTION of tumor suppressor genes that, NOTmembrane FOR SALE glycoprotein, OR DISTRIBUTION a member of the protein kinase

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8 PART I The Cancer Problem

TABLE 1-2

© Jones Somatic& Bartlett Mutations Learning, Associated LLC With Various Types of© CancerJones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Regulatory Gene Types Normal Function Cancer Type(s)

Oncogenes © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC BRAF Produces protein for the RAS/MAPK pathway Somatic mutations causing melanoma, colon, NOTto regulate FOR proliferation SALE OR of DISTRIBUTIONcells, differentiation, rectum, ovarian, andNOT thyroid FOR cancer SALE OR DISTRIBUTION migration, and apoptosis Ras family (H-Ras, Actin cytoskeletal integrity, cell proliferation, Pancreatic cancer N-Ras, K-Ras) differentiation, and apoptosis HER2/neu© Jones & BartlettEpidermal Learning, growth factor LLC ©Breast Jones cancer & Bartlett Learning, LLC MMR genesNOT ( MLH1FOR, SALEMaintain OR DISTRIBUTIONfidelity of DNA during replication NOTColorectal FOR cancer SALE OR DISTRIBUTION MSH2, MSH6, PMS2) Myc Regulatory gene that codes for a transcription Burkitt’s lymphoma factor and regulates global chromatic structure by regulating histone acetylation © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC hTERT Maintains telomere ends, so it is associated with Not specific NOT FOR SALE OR DISTRIBUTIONimmortalization of cells NOT FOR SALE OR DISTRIBUTION Src Participates in engagement of various members Colon cancer, breast cancer, prostate cancer, of tyrosine kinase families metastasis Part of immune response signaling pathways BCL2 ©Helps Jones regulate & Bartlett apoptosis Learning,(anti-apoptosis) LLC Chronic lymphocytic© Jones leukemia, & B-cell Bartlett non- Learning, LLC NOT FOR SALE OR DISTRIBUTION Hodgkin lymphoma,NOT breast FOR cancer, SALE follicular OR DISTRIBUTION lymphoma Tumor Suppressor Genes APC Acts as a tumor suppressor Colon, familial adenomatous polyposis syndrome © Jones & BartlettHelps controlLearning, cell division, LLC attachment to other © Jones & Bartlett Learning, LLC NOT FOR SALEcells OR in tissue, DISTRIBUTION and whether a cell moves within or NOT FOR SALE OR DISTRIBUTION away from a tissue BRCA DNA repair, transcription, and ubiquitination Breast, ovarian, prostate, melanoma, and pancreatic cancer MEN1 Role in repression of telomerase expression Multiple endocrine neoplasia type 1: parathyroid © Jones & Bartlett Learning,Chromatin LLC regulation © Jones & Bartlettcancer, carcinoidLearning, tumors, LLC pancreatic cancer, NOT FOR SALE OR DISTRIBUTION NOT FOR SALEendocrine OR DISTRIBUTION tumors such as pituitary tumor TP53 Conserves stability of the genome and apoptosis Colon, breast, and lung cancer; leukemias, Inhibits angiogenesis lymphomas, and sarcomas; Li-Fraumeni syndrome Activates DNA repair proteins PTEN Promotes apoptosis Cowden syndrome, breast cancer, thyroid cancer, ©Negatively Jones ®ulates Bartlett the AKT/PKBLearning, signaling LLC head and neck cancer,© Jones glioma type& Bartlett 2, prostate Learning, LLC NOTpathway FOR SALE OR DISTRIBUTION cancer, and endometrialNOT cancerFOR SALE OR DISTRIBUTION

Source: Data from Beamer et al2; Rodriguez-Paredes and Esteller39; Hojfeldt et al40; Laird.41

superfamily,© Jones that & penetrates Bartlett the Learning, plasma membrane LLC of the response,© especially Jones &cytokine Bartlett production Learning, and LLCcell survival. cell andNOT binds FOR with SALE epidermal OR growth DISTRIBUTION factor to link extra- When mutated,NOT FOR the EGFR SALE gene OR is associatedDISTRIBUTION with non-small cellular clues to appropriate intracellular responses. As the cell lung cancer (NSCLC).54,55 extracellular ligand binds to the receptor, it triggers dimer- Officially known as “B-Raf proto-oncogene, serine/ ization and phosphorylation, both of which are important threonine kinase,” the BRAF gene transmits extracellu- to activate the stress-associated NF-kappa-B (NF-κB) sig- lar signals to the cell’s nucleus.56 The protein expressed by © Jonesnaling & Bartlett cascade, Learning, ultimately LLCcausing transcription of DNA.© Jones this & gene Bartlett is part Learning,of the RAS/MAPK LLC pathway and is essen- NOT FORThis SALE protein OR is DISTRIBUTIONalso involved with regulation of the immuneNOT FORtial forSALE normal OR prenatal DISTRIBUTION development. Like many other

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proto-oncogenes, it affects proliferation, differentiation, as “driver” mutations) allow thousands of mutations to migration, and apoptosis. When mutated, BRAF is associ- © Jonesoccur, compared& Bartlett with Learning, the lower LLCrates seen with normal © Jones & Bartlett Learning, LLC 43 NOT atedFOR with SALE cancers OR of DISTRIBUTIONthe colon and rectum, ovary, thyroid, NOTcells. FOR Of SALE concern, OR theDISTRIBUTION normal repair mechanisms of and skin (melanoma). The most commonly mutated BRAF direct reversal of DNA damage, excision repair, and post- protein is V600E. It is found in many cancers and is espe- replication repair overlook the DNA damage, leading to cially active in persons born with giant congenital melano- incorrect messages in the DNA sequences, with conse- cytic nevus (GCMN), a large patch of darkly pigmented quently increased probabilities of mutations and growth skin that is considered an especially© Jones high & riskBartlett factor forLearning, can- advantage. LLC 43 © Jones & Bartlett Learning, LLC cer development due to continuousNOT FOR and SALE uncontrolled OR DISTRIBUTION cell NOT FOR SALE OR DISTRIBUTION growth of melanocytes after birth. Somatic missense mutations for BRAF have been identified in 66% of malignant ENABLER: INDUCING INFLAMMATION melanomas.57,58 The oncogene© Jones known & Bartlett as the KRASLearning, gene isLLC officially In 1986, it was© Jonesnoted that & Bartletttumors could Learning, be densely LLC popu- named “Kirsten rat sarcoma viral oncogene homolog.” The lated with both innate and adaptive arms of the immune NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION KRAS gene produces a protein, K-Ras, which is primarily system, and could also mirror inflammatory conditions.64 responsible for regulating cell division through the intracel- Today, technology has enhanced the ability to locate lular RAS/MAPK signaling pathway. This protein travels immune cells in most neoplastic lesions and identify the from the cytoplasm to the nucleus of the cell, where it par- level of penetration, which can range from subtle infil- © Jonesticipates & Bartlett in specialized Learning, functions LLC such as proliferation, dif- © Jonestration to& Bartlettgross inflammatory Learning, processes.LLC Initially it was NOT ferentiation,FOR SALE and OR senescence. DISTRIBUTION Other genes in the Ras family NOTbelieved FOR theseSALE immune OR DISTRIBUTION responses reflected an attempt by include HRAS and NRAS.58,59 the immune system to eliminate the tumors. More recently, The official gene symbol for the “v-myc avian myelocy- it has been documented that antitumor responses to many tomatosis viral oncogene homology” is MYC. Like many types of cancer occur.1 By the turn of the 21st century, proto-oncogenes associated with cancer, MYC is important researchers had realized that the tumor-associated inflam- for progression through the© cell Jones cycle, &apoptosis, Bartlett and Learning, cellu- matory LLC response was able to foster© Jones tumorigenesis & Bartlett and Learning,pro- LLC lar transformation. MYC proteinsNOT FOR function SALE as transcription OR DISTRIBUTION gression. It is now known thatNOT the innate FOR immune SALE responseOR DISTRIBUTION factors to regulate transcription of specific target genes. has influence at the intersection of inflammation and can- MYC gene mutations are associated with hematopoietic cer progression.65–68 tumors, leukemias, and lymphomas, including Burkitt’s When p53 is mutated, it may cause binding of a tumor lymphoma.©60,61 Jones & Bartlett Learning, LLC suppressor protein,© Jones located & Bartlett in the cytoplasm, Learning, to promoteLLC The “cyclin-dependentNOT FOR SALE kinaseOR DISTRIBUTION inhibitor 2A” gene TNFα signalingNOT for FOR activation SALE of OR macrophages DISTRIBUTION and regu- (CDKN2) is also known as p16 (INK4). It produces two lation of other immune cells.69 This mutation affects two major tumor suppressor proteins: p16 (INK4, INK4A) other pathways downstream: NF-κB, to alter the control and p14 (ARF). These proteins regulate the p53 cell-cycle of DNA transcription, and JNK, to diminish apoptosis.70,71 regulatory pathways, causing cell-cycle arrest in the G1 Inflammation also has the capability to supply bioactive © Jonesand G&2 /MBartlett phases; Learning, p14 (ARF) LLC produces similar effects© Jonesmolecules & Bartlettto the tumor Learning, microenvironment, LLC including NOT inFOR the SALEretinoblastoma OR DISTRIBUTION pathway (RB1). Mutations in NOTgrowth FOR factors SALE that OR sustain DISTRIBUTION proliferative signaling; survival either the p16 or p14 protein allow continued movement factors that limit cell death; pro-angiogenic factors; extra- through the G1 and G2/M phases and promote prolif- cellular matrix–modifying enzymes that facilitate angio- eration of the cell. CDKN2A mutations are found in genesis, invasion, and metastasis; and inductive signals that pancreatic cancer and gastrinomas, while mutations in lead to activation of the epithelial–mesenchymal transition © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC p16 are associated with leukemias and bladder cancer. and other hallmark-facilitating pathways.65 – 67,72 Melanoma seems to be associatedNOT FOR with SALE either ORCDKN2A DISTRIBUTION Much research literature nowNOT links FOR inflammation SALE OR associ DISTRIBUTION- or p16 mutations.62,63 ated with chronic disease and observed at the earliest stages of neoplastic progression with nurturing of a budding neoplasia into a dangerous malignancy.67,73 It is well known HALLMARK:© Jones DEFECTIVE & Bartlett DNA Learning, REPAIR LLC that inflammatory© Jones cells &release Bartlett a variety Learning, of chemicals, LLC such AND MAINTENANCENOT FOR SALE OR DISTRIBUTION as reactive oxygenNOT FORspecies SALE (ROS), OR which DISTRIBUTION include oxygen ions, superoxides, and peroxide. These chemicals react with The mutator gene phenotype collects increasing numbers molecules containing oxygen; they can be mutagenic to of mutated genes left unrepaired due to poor proofread- cells in close proximity and can accelerate malignant trans- ing or insertion of incorrect nucleotides (G, C, T, or A). formation.1 The immune cells responsible for this enabling © JonesEfficient & Bartlett at acquiring Learning, mutations LLC in the form of both© Jonestrait are &described Bartlett in theLearning, “Hallmark: LLC Evasion of Immunity” NOT clonalFOR andSALE random OR mutations,DISTRIBUTION mutator genes (also known NOTsection. FOR SALE OR DISTRIBUTION

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ENABLER: INDUCING ANGIOGENESIS of normal stem cells and CSCs.80–82 These specific traits © Jones & Bartlett Learning, LLC © Jonesmay & allow Bartlett cells toLearning, be shed from LLC primary tumors and may NOT FORLimitations SALE OR in theDISTRIBUTION oxygen supply for tumor cells induceNOT FORsupport SALE the self-renewalOR DISTRIBUTION capability of cancer cells that is growth strategies for blood vessels other than just those seen important for clonal expansion at distant sites.83 with embryogenesis. The mutations, mechanical stresses, inflammatory processes, and hypoxia all slant the tumor cells’ growth gradient toward the pro-angiogenic side of CANCER STEM CELL PLASTICITY the equation.74 Specifically,© Jones these &factors Bartlett induce Learning, the growth LLC © Jones & Bartlett Learning, LLC of a heterogeneic and disorganizedNOT FOR SALEnetwork OR of dilated DISTRIBUTION ves- Also noted previously, theNOT phenotypic FOR SALE plasticity OR DISTRIBUTIONof cells sels lined with irregularly shaped endothelial cells that lack within tumors produces bidirectional conversion between the close and continuous contact of normal cells. Hypoxia CSCs and non-CSCs, enabling a dynamic fluctuation in is reinforced by the abnormal vessels and cells, thereby the availability of CSCs. Because this process might enable stimulating© Jones production & Bartlett of vascular Learning, endothelial LLC growth fac- CSCs to ©accumulate Jones & after Bartlett decades Learning, of apparent LLCremission, it tor (VEGF). With the increased availability of VEGF, the suggests a rationale for resistance to chemotherapy or exac- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION endothelial cells are instructed, via D114/notch signaling, erbation of disease after long-term remission/latency.80,84–86 to grow vessel sprouts that lack normal pericytes to regu- Inherent in this rationale is the threat that the CSCs might late normal blood flow; these defective blood vessels lead be more treatment resistant and have the ability to regener- to poor vessel function and enhanced tumor hypoxia.75 In ate once treatment has been stopped.1 © Jonesthe & Bartlettface of these Learning, defects, the LLC need for oxygen is enhanced,© Jones Phenotypic& Bartlett plasticity Learning, also suggestsLLC that functionally dis- NOT FORpromoting SALE OReven DISTRIBUTION more growth of abnormal vessels withNOT- FORtinct subpopulationsSALE OR DISTRIBUTION might form within the tumor that sup- out the capability to supply an already oxygen-deficient port tumor growth. Two examples are epithelial carcinoma endothelium. A vicious cycle without potential for rescue cells, which are converted into mesenchymal, fibroblast- is created.76 Of note, this process causes the cancer cell to like cancer cells that assume the duties of cancer-associated have poor sensitivity to chemotherapy and resistance to fibroblasts (CAFs), and glioblastoma cells, which have been radiation.77 © Jones & Bartlett Learning, LLCfound to transdifferentiate© Jones into endothelial-like & Bartlett Learning, cells to LLC NOT FOR SALE OR DISTRIBUTIONform tumor-associated neovasculature.NOT FOR SALE87–89 Tumor OR progresDISTRIBUTION- sion with a variety of cell subpopulations might, therefore, HALLMARK: MICROENVIRONMENT be due to rapid genetic diversification that outperforms the capability of tumor elimination by treatment.1 ENABLER:© Jones CANCER & Bartlett STEM CELLS Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION The oncogenic and tumor suppressor mutations that define DRIVER: TELOMERASE cancer as a genetic disease are present within the cancer cells and have the capability to initiate and drive tumor progres- Cancer stem cells are known to have increased levels of sion. Although these mutations were originally believed to telomerase and thus have an extended life enhanced by the © Jonesbe & presentBartlett only Learning, in hematologic LLC cancers, advances in tech© -Jonesprotected & Bartlett telomeres Learning, at the ends LLC of the chromosome. This NOT FORnology SALE have OR enabled DISTRIBUTION the researcher and the practitionerNOT to FORenzyme SALE also protectsOR DISTRIBUTION the cell from apoptosis.90 obtain information about the intratumor heterogeneity and the subclasses of neoplastic cells, known as cancer stem cells (CSCs), found within tumors. CSCs have the ability to ENABLER: IMMUNE RESPONSE CELLS proficiently seed new tumors, complete with new and nor- © Jones & Bartlett Learning,1,78,79 LLC © Jones & Bartlett Learning, LLC mal markers associated with the tissue of origin. The Immune cells are also found within the microenviron- origin of CSCs is unknown;NOT FORindeed, SALE it seems OR to DISTRIBUTIONvary from ment of the tumor. TheyNOT can FOR take SALE the forms OR DISTRIBUTIONof both one tumor type to another. It is unclear whether multiple tumor-antagonizing and tumor-promoting leukocytes, different populations of cell types are present, or whether which are found in most cancers. Since the 1990s, it has some multistep progression yields specific cell types at cer- become apparent that immune cells are present in cancer tain stages© Jones of tumor & Bartlett progression. Learning,1 LLC and that© they Jones promote & Bartlett tumor progression. Learning, In LLC fact, given NOT FOR SALE OR DISTRIBUTION the amountNOT of FOR chronic SALE inflammation OR DISTRIBUTION identifiable within tumor formations, some literature describes tumors as ENABLER: EPITHELIAL–MESENCHYMAL TRANSITION “wounds that never heal.”64,91 These “wounds” harbor tumor-promoting inflammatory cells that include macro- As briefly noted previously, the epithelial–mesenchymal phage subtypes, mast cells, neutrophils, and T and B lym- © Jonestransition & Bartlett (EMT) Learning, allows tumorsLLC to acquire CSC traits,© Jones phocytes. & Bartlett Collectively, Learning, these LLCcells induce and sustain the NOT FORespecially SALE self-renewalOR DISTRIBUTION and antigenic phenotypes like thoseNOT FORdevelopment SALE ORof tumors DISTRIBUTION and proliferation of cancer cells. As

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CHAPTER 1 Biology of Cancer 11

the malignant cells gain access to the margins of the tumor, Limitless replication is also associated with the expres- © Jonesresearch & Bartlettshows these Learning, differentiated LLC immune cells promote © Jonession of &an Bartlett enzyme thatLearning, prevents LLC the destruction of the NOT tissueFOR invasion SALE andOR supportDISTRIBUTION the dissemination and seeding NOTtelomeres—namely, FOR SALE OR telom DISTRIBUTIONerase. Because telomeres protect of the malignant cells.92–96 chromosomes, cells with increased telomerase are known Partially differentiated myeloid progenitors have to be associated with longer telomeres and greater longevity also been identified in tumors.95 Specifically, a group of of cell life. Shorter telomeres, by comparison, are associ- tumor-infiltrating myeloid cells that express the macro- ated with a shorter life span. Cancer stem cells are known phage marker CD11b and ©the Jones neutrophil & Bartlett marker Gr1 Learning, have to LLC have increased levels of telom© Joneserase, with & Bartletttheir extended Learning, LLC been shown to exert immunosuppressiveNOT FOR SALE effects OR by DISTRIBUTION para- life span being enhanced by theNOT protective FOR SALEtelomeres OR at DISTRIBUTIONthe lyzing cytotoxic T lymphocytes (CTLs) and decreasing chromosome ends. Telomerase also assists in protecting the natural kill (NK) cell activity.96,97 These tumor-promoting cell from apoptosis, thereby preventing the death of malig- cells are designated as myeloid derived suppressor cells nant cells.101 98–100 (MDSCs).© Jones & Bartlett Learning, LLC Mitogenic© (growth) Jones signals& Bartlett to cancer Learning, cells are acquiredLLC through a number of mechanisms. For example, production NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION of growth factors (ligands) that attach to cell membrane ENABLER: SIGNALING MOLECULES receptors may stimulate the growth of cancer cells. Usually these ligands are tyrosine kinase receptors (TKRs), which In addition to the presence of inflammation-associated branch into multiple intercellular signaling pathways. © Jonesimmune & Bartlett cells, certain Learning, signaling molecules LLC stimulate and sup- © JonesAs the TKRs& Bartlett are stimulated Learning, outside LLC the cell, the signals NOT portFOR the SALE cancer OR cell DISTRIBUTIONactivities. These include tumor growth NOTcross FOR the cellSALE membrane OR DISTRIBUTION and continue on intracellular path- factors (e.g., epidermal growth factor [EGF]), VEGF, che- ways that are critical for cell-survival factors. Specifically, mokines, and cytokines that have the ability to enhance two kinases—phosphatidylinositol-3-OH kinase (PI3K) inflammation, once again supporting the ever-changing and mitogen-activated protein kinase (MAPK)—are tar- nature of cancer. Factors that promote the degradation of the geted. Because there are more than 20 families of TKRs, © Jones & Bartlett Learning,once LLC they are phosphorylated ©to Jonesthe active & state, Bartlett they affect Learning, LLC cellular matrix (e.g., metalloproteinasesNOT FOR [MMPs],SALE OR cathepsin DISTRIBUTION NOT FOR SALE OR DISTRIBUTION proteases, and heparanase) are also produced and influence a variety of tissue needs. If the TKR signals become stuck further cell changes that support the evolving life of the in the “on” position, unregulated cellular proliferation malignant cell.1,67,95 occurs; this process is a precursor for cellular transformation. (Table 1-3).102–107 © Jones & Bartlett Learning, LLC Signals can© alsoJones originate & Bartlett from cancer Learning, cells and LLCtravel to NOT FOR SALE OR DISTRIBUTION normal cells, NOTall within FOR tumor-associated SALE OR DISTRIBUTION connective tissue. HALLMARK: DEREGULATED GROWTH The normal cells then respond to the ligands by supplying AND MITOGENESIS various growth factors to the malignant cells for supple- mentation of their proliferation requirements.1,14 These The continuous proliferation and deregulated growth of RTK-ligands and pathways are viewed as mechanisms for © Jonescells is& the Bartlett best-known, Learning, albeit poorly LLC understood, character- © Jonescurrent &and Bartlett potential Learning, treatments. LLCBecause malignant cells NOT isticFOR of SALEcancer cells. OR NormalDISTRIBUTION cells are controlled by multiple NOTproduce FOR ectopic SALE hormones, OR DISTRIBUTION growth factors, and cytokines, growth factors and other chemical signals that direct entry an increase in RTK-ligand levels could potentially confer into and out of the phases of the cell cycle. resistance to inhibitors of an oncogenic kinase.108

TABLE 1-3 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Tyrosine Kinase ReceptorsNOT and FORTheir SALEActivity OR Status DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Function RTK Class Type Acronym Function (Increased) (Decreased) © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC I107 Epidermal EGFR, HER2, HER3, HER4 Malignancies (e.g., breast, Alzheimer’s disease, NOTgrowth FOR factors SALE OR DISTRIBUTION pancreatic)NOT FOR SALE OR multipleDISTRIBUTION sclerosis II107 Insulin receptors InsR, IGF-1, InsRR Malignancies (e.g., breast, Diabetes prostate) III107 Platelet derived PDGFRa, PDGFR, Kit/SCFR, Breast cancer Reduces © Jones & Bartlett Learning, LLCFit3/fit2b, CSF1r/Fms © Jones & Bartlett Learning, LLChypertension NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION (continues)

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12 PART I The Cancer Problem

TABLE 1-3

© Jones Tyrosine& Bartlett Kinase Learning, Receptors LLC and Their Activity Status© (Jonescontinued & )Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Function RTK Class Type Acronym Function (Increased) (Decreased)

IV104,107 Vascular endothelial VEGFR1/Fit1, VEGFR2/KDR, Metastatic disease Acute graft-versus- growth factor© Jones & VEGFR3/Fit4Bartlett Learning, LLC © Jones &host Bartlett disease, Learning, LLC NOT FOR SALEEpithelial OR proliferation DISTRIBUTION and NOT FOR myopicSALE choroidal OR DISTRIBUTION angiogenesis neovascularization → retinal detachment V102,103,107 Fibroblast growth FGFR1, FGFR2, FGFR3, FGFR4 Malignancies (e.g., pancreatic, Hypophosphatemia © Jonesfactor & receptorBartlett Learning,Angiogenesis LLC and wound healing esophageal,© Jones prostate) & Bartlett Learning,in renal disorders LLC NOT FOR SALE OR DISTRIBUTIONImmunoglobulin superfamily NOT FOR SALE OR DISTRIBUTION due to immunoglobulin-like extracellular domains VI107 Hepatocyte GF Wound healing (angiogenesis) Renal cell cancer, hypertension, Unknown Metastasis arteriosclerosis, myocardial © Jones & Bartlett Learning, LLC © Jones &infarction, Bartlett rheumatoid Learning, arthritis LLC NOT FORVII 107SALE ORTrk DISTRIBUTION receptor family NGF/neurotrophin receptorNOT TrkAFOR SALE OR DISTRIBUTION Nerve growth factor Nervous system VIII107 Epithelial receptor EphA1-8, EphA10, EphB1-4, Melanoma, breast, prostate, family EphB6 pancreatic, gastric, esophageal, © Jones & Bartlett Learning, LLC and colon cancer; hematopoietic© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION tumors NOT FOR SALE OR DISTRIBUTION IX107 Axl receptor family— Axl, Mer, Tyro3 Chronic myelogenous leukemia, located close to the Stimulation of cell proliferation colon cancer, and melanoma; BCL3 oncogene at Mediation of cell aggregation breast cancer metastasis 19q13.1–q13.2 X107 © JonesLTK &receptor Bartlett family Learning,LTK, ALK LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONCell growth and proliferation NOT FOR SALE OR DISTRIBUTION XI107 TIE receptor family Tie1, Tie2 Angiopoietin XII102,106 ROR receptor family Ror1, Ror2 Cell motility © Jones & Bartlett Learning, LLC Regulation of skeletal© and Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION neuronal development,NOT cell FOR SALE OR DISTRIBUTION migration, and cell polarity Modulation of Wnt signaling XIII107 DDR receptor DDR1 (CD167a), DDR2 Malignancies (e.g., breast, family(discoidin© Jones & 6p21.3Bartlett location Learning, LLC ovarian, esophageal, pediatric© Jones & Bartlett Learning, LLC domain receptor) brain) NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION XIV105,107 RET receptor family Ret proto-oncogene Multiple endocrine neoplasia type 2 (MEN2A, MEN2B, familial medullary thyroid carcinoma), pheochromocytoma, parathyroid © Jones & Bartlett Learning, LLC hyperplasia© Jones & Bartlett Learning, LLC XV107 NOT FORKLG receptorSALE ORfamily DISTRIBUTIONSignal transduction ColonNOT carcinomas FOR SALE OR DISTRIBUTION PTK7 gene Cell adhesion molecule XVI107 RYK receptor family No phosphorylation occurs at Leukemia this receptor XVII107 MuSK receptor family Neuromuscular junction and © Jones & Bartlett Learning, LLC synapse © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Source: Data from Forrester102; Imel and Econs103; Sawada et al104; Green et al105; Moline and Eng106; Lemmon and Schlessinger.107

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CHAPTER 1 Biology of Cancer 13

Deregulation of the growth factor receptor signaling can Normally oxygenated cancer cell occur by increasing the levels of receptor proteins displayed 1 glucose molecule 36 molecules ATP © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning,+ LLC NOT onFOR the surfaceSALE membrane OR DISTRIBUTION of the cancer cell. Increased levels NOT FOR SALE OR DISTRIBUTION of receptor proteins cause the malignant cells to become 10 glucose molecules 20 lactic acid molecules hyperresponsive to the amount of growth factor available. 20 ATP molecules Sometimes the receptor molecule has a structural alteration TOTALS = 56 ATP molecules that facilitates ligand-independent firing, again causing deregulated growth.1 © Jones & Bartlett Learning,Unoxygenated LLC cancer cell © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION13 glucose molecules NOT 26 molecules FOR SALE lactic acid OR DISTRIBUTION 26 ATP molecules HALLMARK: METABOLIC PROGRAMMING TOTALS = 26 ATP molecules

Early scientists believed alterations in metabolic reprogram- © Jones & Bartlett Learning, LLC NORMAL oxygenated© Jones cell & Bartlett Learning, LLC ming initiated the transformation of the normal cell into NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION the malignant cell.109 Today it is well known that altera- 1 glucose molecule 36 molecules ATP tions in the tumor suppressors and oncogenes have intimate TOTALS = 36 ATP molecules connections with metabolic pathways. Changes in these FIGURE 1-1 pathways are now recognized to be secondary results, how- © Jonesever, rather& Bartlett than primary Learning, causes LLC of carcinogenesis.110–114 In © JonesATP production & Bartlett in cancer Learning, cells versus LLC normal cells. NOT addition,FOR SALE early ORscience DISTRIBUTION theory suggested aerobic glycolysis NOTSource: FOR Data fromSALE Warburg OR110,111 DISTRIBUTION; Keilin116; Racker.117 occurred instead of mitochondrial respiration.111–113 Work in the laboratory has shown that many cancers retain mitochondrial respiration for energy production while also rely- ing on aerobic glycolysis.114 In tumors, 66% of the glucose consumed is changed As in the normal cell,© theJones need & for Bartlett energy Learning,in the to LLC lactic acid; by comparison,© in Jones healthy & cells Bartlett there isLearning, no LLC cancer-causing cell can be addressedNOT FOR through SALE the OR increased DISTRIBUTION net production of lactic acid.NOT Cancer FOR cells SALE can “recycle”OR DISTRIBUTION use of glucose transport molecules, such as GLUT1, to lactic acid under aerobic conditions. This ability to recycle bring glucose into the cytoplasm or provide glucose that lactic acid may be altered depending on the proximity of can be converted into lactic acid.115 When they have glucose the cancer cell to arterial versus venous blood. Metabolism available to© them, Jones cancer & Bartlett cells have Learning, the capability LLC to repro- occurring in ©close Jones proximity & Bartlett to arterial Learning, blood may LLCbe more gram theirNOT metabolism FOR SALEdepending OR on DISTRIBUTION the oxygenation sta- rapid due to NOTthe movement FOR SALE of oxygen OR DISTRIBUTIONassociated with the tus of the tissues. Oxygenated cancer tissue will metabolize oxygenation gradient, whereas metabolism closer to venous one molecule of glucose to yield 36 adenosine triphosphate blood may be limited by diffusion.114,120 This concept is the (ATP) molecules, like a normally oxygenated cell, but also basis for the popular understanding that tumor cells’ inte- convert 10 more glucose molecules to 20 molecules of lactic rior necrosis results from the presence of fewer and highly © Jonesacid through& Bartlett metabolism. Learning, Because LLC lactic acid is converted © Jonesfragile blood & Bartlett vessels to Learning, carry oxygenated LLC blood. NOT toFOR ATP SALE at a 1:1 ORratio, DISTRIBUTION a total of 56 molecules of ATP become NOT FOROxidative SALE phosphorylation OR DISTRIBUTION (OXPHOS) is the metabolic available in the oxygenated cancer cell through this process. pathway of the mitochondria involved in respiration and ulti- During poorly oxygenated conditions, the cancer cell will mately in ATP generation after oxidation of nutrients. The convert 13 glucose molecules to 26 ATP molecules. In the oxidation–reduction (redox) reaction link between metabo- time that a normal cell is able to metabolize 36 ATP mole- lism and tumorigenesis was confirmed when mutations of © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC cules for use by the cell, the oxygenated cancer cell generates oncogenes were identified for three mitochondrial metabolic 56 ATP molecules while theNOT anaerobic FOR cancer SALE cell OR generates DISTRIBUTION enzymes: fumarate hydrataseNOT (FH), FOR succinate SALE dehydroge OR DISTRIBUTION- 26 such molecules (equivalent to the production of the nor- nase (SDH), and isocitrate dehydrogenase 2 (IDH2).114,121 mal cell).109–111,116,117 Figure 1-1 illustrates the calculations Two cancers associated with the mutated SDH enzyme of ATP production in cancer cells versus normal cells. These are the rare hereditary paragangliomas and pheochromo- simplified,© yetJones important & Bartlett calculations Learning, are the rationaleLLC for cytomas.114,122© MutationsJones & ofBartlett FH, which Learning, is involved LLC with the use of positronNOT FOR emission SALE tomography OR DISTRIBUTION (PET) scanning to the citric acidNOT cycle FORdownstream SALE of OR SDH, DISTRIBUTION result in familial detect the higher levels of glucose in the tumor than in the leiomyoma, renal cell carcinoma, and uterine fibroids. As adjacent tissues.118 Put succinctly, even in nonhypoxic con- the damaged FH and SDH levels rise, another enzyme is ditions cancer cells can produce lactic acid from glucose.117 inhibited, causing modifications of hypoxia-inducing fac- In addition to the energy needed for a normal cell, these tor alpha (HIF-α) and its degradation in the presence of © Jonesmechanisms & Bartlett can make Learning, a net increase LLC of approximately 13% © Jonesoxygen. &Tumor Bartlett development Learning, ensues LLC as HIF-α levels become NOT moreFOR energy SALE available OR DISTRIBUTION to the malignant cell.119 NOTelevated. FOR123 SALE OR DISTRIBUTION

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Somatic mutations of the proteins IDH1 (cystolic) and expression of the GLUT1.118,134 Loss of p53 sensitizes the © JonesIDH2 & Bartlett (mitochondrial) Learning, are LLCalso associated with OXPHOS© Jones tumor & Bartlettcell to treatment Learning, with drugsLLC that affect metabolism NOT FORmutations. SALE ORApproximately DISTRIBUTION 80% of low-grade gliomas andNOT FOR(e.g. metformin)—anSALE OR DISTRIBUTION interesting option for further cancer 30% of karyotypically normal acute myelogenous leuke- treatment research into the metabolic pathways. mias demonstrate these IDH1 and IDH2 mutations.124,125 During the regulation of metabolism, p53 communi- Both IDH1 and IDH2 are part of an enzyme cascade that, cates with other cancer-associated signaling pathways linked when mutated, alters the homeostasis of a substrate for with metabolism, such as MYC, HIF1, and Akt. Figure 1-2 enzymes that methylate© DNAJones and & histones.Bartlett Modification Learning, LLCdepicts how the oncogenes© Jones Myc, Akt &, Bartlettand Ras signalLearning, an LLC of these components ofNOT the FORepigenome SALE enhances OR DISTRIBUTION tumori- increase in glycolysis throughNOT the FOR activation SALE of OR enzymes DISTRIBUTION in genesis, yet mutations in OXPHOS genes affect only a lim- the different pathways.113,117 HIF can inhibit oxygen con- ited number of cancer types.114,126,127 sumption and increase glycolysis. At times the Src oncogene In human cancers, somatic mutations may occur in the will target HIF in some tumor types. Finally, the tumor mitochondrial© Jones DNA & Bartlett (mtDNA). Learning, Recently, LLC heteroplasmy suppressor© Jonesp53 can &both Bartlett inhibit Learning, glycolysis and LLC promote (i.e., a mixture of mutant and normal mtDNA within a mitochondrial respiration.114,118 The hypoxic conditions NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION single cell) in cancer-causing cells versus normal cells has found in cancer cells also mobilize the glucose transporters been the focus of research. When mutations in embry- with HIF-1α and HIF-2α to “turn on” glycolysis.130–132,135 onic cells were compared to mutations in the same regions Although normal cells and cancer cells utilize similar of cancer cells, the protein coding regions were found to metabolic pathways, the malignant cells are “addicted” to © Jonesmake & Bartlett up 33% Learning, and 85% of LLCthese areas, respectively. These© Jones using & bothBartlett glycolysis Learning, (with fermentation LLC of glucose to lac- NOT FORresults SALE suggest OR DISTRIBUTIONthat endogenous mutagenic events occurNOT FORtate secretion)SALE OR and DISTRIBUTION mitochondrial respiration, even in the normally and that the somatic mutations of mtDNA are presence of oxygen, to provide energy (ATP) to the rapidly enriched, perhaps conferring a selective advantage for sur- growing cancer cell.136 It is now recognized that this altered vival and growth.128 Another study identified heterogeneity metabolic programming phenotype of the cancer cell is due across tumor types but found a significantly higher num- to the mutations and altered gene expression of tumor sup- ber of mutations in the© gastrointestinalJones & Bartlett and hepatobiliary Learning, LLCpressors and oncogenes.137© Jones & Bartlett Learning, LLC systems, emphasizing NOTthe fragility FOR ofSALE the mismatch OR DISTRIBUTION DNA NOT FOR SALE OR DISTRIBUTION repair system in the GI tract.129 It is now believed that changes in cancer cell metabolism HALLMARK: SUPPRESSION OF APOPTOSIS extend beyond those addressing the increased anabolic needs of a growing© Jones and &dividing Bartlett cell. Learning,Some evidence LLC suggests that DRIVER:© DECREASED Jones & Bartlett CELL ATTRITION Learning, LLC variationsNOT in FOR both SALEoncogenes OR and DISTRIBUTION tumor suppressor genes NOT FOR SALE OR DISTRIBUTION cause reprogramming of metabolic enzymes that can then In the normal cell, apoptosis is induced by a number of affect the differentiation of the cell.6 The glycolytic fueling pathways, both intrinsic and extrinsic. One mechanism is process seen with the metabolic reprogramming of the cancer a DNA-damage sensor that works via TP53. This tumor cell is associated with activated oncogenes (AKT, R AS, and suppressor gene increases production of apoptotic pro- © JonesMYC & Bartlett) as well asLearning, mutated tumor LLC suppressor genes (TP53).130–132© Jones teins, & suchBartlett as NOXA, Learning, when significantLLC numbers of DNA NOT FORIt isSALE well known OR DISTRIBUTION that these altered genes are also associatedNOT FORbreaks SALE and other OR chromosomalDISTRIBUTION abnormalities are detected. with cell proliferation and avoidance of cell death. Insufficient signaling due to inadequate interleukins (from The first oncogene found to be associated with altered lymphocytes) or insulin-like growth factor (from epithelial glucose metabolism was MYC.132 It activates glycolytic cells) will prompt apoptosis. Hyperactive signaling by onco- enzyme genes and glucose transporter genes as well as the proteins like Myc is another common trigger. Interruption © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC splicing factors that produce PKM2—that is, the enzyme of any of these mechanisms will lead to suppression of pyruvate kinase that catalyzesNOT FOR the last SALE step inOR glycolysis. DISTRIBUTION131 apoptosis and prolonged cellNOT life, FOR with SALEthe accumulation OR DISTRIBUTION of Other research suggests that MYC can stimulate the aerobic severe or irreparable genetic abnormalities ultimately lead- glycolysis associated with HIF-1α, even though it is more ing to tumorigenesis. commonly associated with anaerobic glycolysis.133 The Ras oncogene© Jones stimulates & Bartlett glucose uptake. Learning, Depending LLC on the cell © Jones & Bartlett Learning, LLC type, NOTthe Src FOR oncogene SALE may OR also DISTRIBUTION be involved in the activa- ROLE OFNOT POTASSIUM, FOR SALE SODIUM, OR DISTRIBUTION tion of HIF-1α to promote glycolysis.114 AND CALCIUM IONS The tumor suppressor genes also have the capability to alter metabolic programming. Thep53 tumor suppressor, While potassium has a role in cell proliferation, differ- known as the “guardian of the genome,” acts as the first entiation, regulation of cell volume, and maintenance of © Jonesline & Bartlettof defense Learning, against glucose LLC uptake by preventing ©the Jones membrane & Bartlett potential, Learning, several of LLC the potassium channels fill NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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CHAPTER 1 Biology of Cancer 15

Metabolism Tumor Suppressor Oncogenes Gene © Jones & Bartlett Learning, LLC Pathw©ay Joness & Bartlett(Anti-oncogene Learning,) LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Glutaminolysis Myc (Glutamine Metabolism) © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Akt

Ras

(Cellular O2 Consumption)

NOTSrc FOR SALE OR DISTRIBUTION Increases or promotesNOT FOR SALE OR DISTRIBUTION Inhibits

FIGURE 1-2

© Jones &Role Bartlett of oncogenes Learning, and the LLCp53 tumor suppressor gene in ©metabolism. Jones & Bartlett Learning, LLC NOT FOR SALESource: Data OR from DISTRIBUTIONKoppenol et al114; Cheung and Vousden.118 NOT FOR SALE OR DISTRIBUTION

© Jonescritical & rolesBartlett during Learning, apoptosis.138 LLC Positively charged sodium © JonesOne &type Bartlett of indolent Learning, (slow-growing) LLC non-Hodgkin NOT anFORd calcium SALE channels OR DISTRIBUTION of normal cells contribute to apopto- NOTlymphoma, FOR SALE known OR as DISTRIBUTIONfollicular lymphoma, demonstrates sis.138,139 Alterations of these ionic channels across the cell the effects of loss of apoptosis. This lymphoma accounts membrane affect the status of the cell. Loss of potassium, for approximately 20% of all non-Hodgkin lymphomas. for example, causes loss of cell volume and cell shrink- It is frequently associated with a rearrangement of the age. Such a loss of intracellular potassium can activate the BCL2 gene. Continued proliferation of the follicular cells © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC caspase cascade and other apoptotic changes. Conversely, is caused by increased expression of the bcl2 protein due to intracellular levels of sodiumNOT increase FOR early SALE in the OR cell DISTRIBUTIONdeath this genetic mutation; the greaterNOT production FOR SALE of theOR bcl2 DISTRIBUTION process.129,138,139 Movement of chloride, an anion conduc- protein hinders apoptosis, making it difficult for the fol- tor, has been shown to increase or decrease apoptosis.140 licular lymphoma to be destroyed.142 After the initial caspase activation triggers apoptosis, Multiple pathways and diverse apoptotic mechanisms the second© pathway Jones of& apoptosis-inducingBartlett Learning, factors LLC such as need to be overcome© Jones for & a Bartlettcell to attain Learning, malignant LLC status. cytochromeNOT C and FOR other SALE mitochondria-derived OR DISTRIBUTION activators It is hypothesizedNOT that FOR restoration SALE ORof apop DISTRIBUTIONtosis may provide stimulates the release of more caspases. Resistance to these an approach to cancer therapy, perhaps through a means as mechanisms of apoptosis occurs once the cell detaches simple as potassium therapy.141,142 Sequential application and from its neighboring cells and becomes metastatic. Many combinations of anticancer drugs with natural ingredients other signaling pathways that are as yet unknown are have been shown to enhance cell death by gene enhance- © Jonesalso suspected& Bartlett to playLearning, roles in thisLLC process.139,141 © Jonesment and & rewiringBartlett apoptotic Learning, signaling LLC networks.32,143 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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16 PART I The Cancer Problem

HALLMARK: EVASION OF SENESCENCE phenotypes—a characteristic that makes them attractive © Jones & Bartlett Learning, LLC © Jonestargets & Bartlett for personalized Learning, medicine. LLC For example, miR-17 NOT FORSenescence SALE OR is a stressDISTRIBUTION response that blocks cell proliferationNOT FORand miR-21 SALE areOR upregulated DISTRIBUTION in colon, lung, stomach, pros- and prevents tumor progression in normal cells. Research tate, and pancreatic tumors, while miR-155 is upregulated in animal models and humans shows that premalignant in breast, lung, and colon cancers. Other miRNAs, such senescence needs to be overcome if the cell is to evolve as miR-15-a and miR-16-1, are downregulated in chronic into a malignant state.144 If the capacity for senescence is lymphocytic leukemia (CLL), prostate tumors, and pitu- impaired, this stress response© Jones can & be Bartlett “forced” Learning,into action LLCitary adenomas. Current ©speculation Jones & suggests Bartlett upregulated Learning, LLC by bypassing an importantNOT oncogenic FOR SALE pathway OR or DISTRIBUTION restoring miRNAs act as oncogenesNOT and lostFOR miRNAs SALE as OR tumor DISTRIBUTION sup- damaged tumor suppressors. These mechanisms that can pressors. However, much remains unknown about these 151 reverse or clear senescence are potential avenues for devel- tiny molecules. opment of new drugs, prognostic markers, and targeted therapies© Jones for personalized & Bartlett medicine. Learning,144 LLC © Jones & Bartlett Learning, LLC 145 HALLMARK: EVASION OF IMMUNITY HayflickNOT FOR and SALEMoorhead OR first DISTRIBUTION identified that normal NOT FOR SALE OR DISTRIBUTION cells have a finite number of cellular divisions that they can experience before they rest, “long term,” from cycling. Surveillance by the immune system is believed to be a Senescence is now believed to be due to a lack of reaction to real-time, vigilante mechanism that monitors for emergent growth factor stimulation, unsustainable metabolic activity, cancer cells and destroys most of them before they are able © Jonesand & Bartlettchanges in Learning, the morphology LLC of the cell, including dimin© -Jonesto develop & Bartlett into a Learning, rapidly growing LLC tumor. While this seems NOT FORished SALE length OR of telomeresDISTRIBUTION associated with a lack of RNaseNOT H FORlogical SALE when ORcontemplating DISTRIBUTION the increased number of can- and reduced or inactivated telomerase activity.145–147 cers in immunocompromised hosts, most of these cancers are associated with viral-initiated cancers, such as Kaposi’s sarcoma.152 More than 80% of malignancies have nonviral ONCOGENES AND TUMOR SUPPRESSOR GENES causes, and current research suggests the immune system © Jones & Bartlett Learning, LLCrepresents a significant barrier© Jones to tumor & Bartlett formation Learning, and pro- LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Activation of oncogenes or loss of tumor suppressor genes gression, especially for those cancers associated with viruses. such as PTEN, RB1, NF1, and INPP4B can also trigger Among individuals who have deficiencies in the development senescence.148 When these tumor suppressors check for or function of the cells that direct the presentation, process- stress signals in the normal cell, they can sense other pro- ing, or destruction of the foreign tissue/antigen (CD4+ Th1 teins responsible© Jones for & signalingBartlett the Learning, need for production LLC of dif- helper cells,© Jones CD8+ & cytotoxic Bartlett T Learning, lymphocytes, LLC or natural 153,154 ferent NOTproteins FOR necessary SALE to ORtrigger DISTRIBUTION senescence. Mutation of killer cells),NOT there FOR is an SALE increased OR incidence DISTRIBUTION of tumors. the tumor suppressor genes can prevent senescence, allowing Lectins are types of glycoproteins that enable carbohy- malignant activation in the cell to occur. Senescent tumor cells drate binding and other biological activities such as immu- 155 can be eliminated through pro-senescence therapy, including nomodulatory activities and antitumor effects. Upon efficient removal of these tumor cells by the immune cells.149 recognition of a foreign agent, binding proteins on the cell © Jones & Bartlett Learning, LLC © Jonesmembrane & Bartlett initiate Learning, the lectin pathwayLLC of complement acti- NOT FOR SALE OR DISTRIBUTION NOT FORvation SALE by attaching OR DISTRIBUTION proteases to the invaders. The resulting NONCODING RNAS direct opsonization (binding to a phagocyte), neutralization, and agglutination limit the attack and concurrently direct a Research that targets noncoding RNAs is beginning to follow-up adaptive immune response.156 Any alterations in lectin binding, however, enable leukocytes to adhere to and enhance our understanding© Jones of senescence. & Bartlett For Learning, example, LLC © Jones & Bartlett Learning, LLC miR-20a has the ability to promote senescence induction cover malignant cells. This change allows the malignant cell through the downregulationNOT FOR of lymphoma-related SALE OR DISTRIBUTION factor to escape surveillance andNOT travel FOR to distant SALE sites OR in the DISTRIBUTION body (LRF, also known as ZBTB7A).150 under the guise of a bolus of normal and abnormal cells.1

MICRORNAS© Jones & Bartlett Learning, LLC HALLMARK:© Jones DISRUPTION & Bartlett Learning,OF EPITHELIAL LLC NOT FOR SALE OR DISTRIBUTION ADHESIONNOT FORAND SALEPOLARITY OR DISTRIBUTION Multiple miRNAs have been identified as having regulatory functions important to genetic control mechanisms DRIVER: ACTIVATING INVASION AND METASTASIS and are known to be deregulated in cancer. Approximately 18 to 25 nucleotides in length, these microRNAs regulate Normal epithelial cells are held in place within the tissues © Jonesthe & Bartlettexpression Learning, of a variety LLC of genes.150,151 Many of them© Jones through & Bartlett tight junctions Learning, and adhesion LLC molecules. The adhe- NOT FORhave SALE been ORshown DISTRIBUTION to have specific roles in various tumorNOT FORsion ofSALE cells causes OR DISTRIBUTION tight binding of cells to each other, such

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CHAPTER 1 Biology of Cancer 17

that ions are unable to pass through a space between the charge. A variety of changes affect the phospholipid con- cells. Transmembrane proteins, such as integrin and cad- © Jonestent during & Bartlett membrane Learning, synthesis of LLC the neoplastic cell as it © Jones & Bartlett Learning, LLC157 164 NOT herin,FOR support SALE theseOR DISTRIBUTIONtight junctions. NOTmoves FOR through SALE the OR ongoing DISTRIBUTION progression of the cell cycle. Integrin has two types of functional subunits (α and β) Most changes of the phospholipid content occur based and selectively binds to the extracellular membrane to the on cell type, pH of the membrane, and the growth phase cell by identifying three specific amino acids. These sub- and transformation status of the malignancy. Amino acid units are present in multiple forms to promote function- components (which have their own electrical charges) of ality, including transferring© Jonesinformation & Bartlett into the Learning, cell, the LLC phospholipid membrane affect© Jones the &membrane’s Bartlett chargeLearning, LLC with diverse tissues and theirNOT adhering FOR SALE companions. OR DISTRIBUTION The such that it is increased at bothNOT low FOR pH (acidic,SALE negativeOR DISTRIBUTION intercellular adhesion molecule, cadherin, binds the same charges) and high pH (basic, positive charges).18 Once type of cells to each other with the additional function cells detach from their neighborhood of cells and other of information transference. These normal cells will not anchorage-dependent cells, they can evade apoptosis and 141 respond to© mitogens Jones as& longBartlett as they Learning, are restrained LLC by the are capable of© tumorigenesis. Jones & Bartlett Changes Learning, in the charge LLC of cadherin-associated contact inhibition and continue to the cell membrane inhibit apoptosis, contribute to the lon- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION support the cellular matrix with integrins. Malignant cells, gevity of the malignant cell, and increase the loss of contact in contrast, no longer respond to the controls of the cad- inhibition, thereby enhancing the ability to of the cell to herin and integrin molecules as they come in contact with spread, invade, and metastasize. mitogens.157 © JonesThe & Bartlettintegrins areLearning, activated LLCby Src family kinases (SFK), © Jones & Bartlett Learning, LLC NOT sometimesFOR SALE in combinationOR DISTRIBUTION with receptor tyrosine kinase NOTHALLMARK: FOR SALE MATRIX OR DISTRIBUTION DEGRADATION (RTK) signaling molecules such as ErbB2 and Met; they AND GAIN IN MOTILITY energize the cytoplasmic tail of E-cadherin molecules to tag them for degradation. The machinery of the SFKs regulates Like normal cells, the malignant cell has proteins, glyco- essential processes of the cell such as cell growth, differen- proteins, and glycolipids with altered mobility on the sur- tiation, migration, and survival;© Jones cell shape; & Bartlett and specialized Learning, face LLC membrane. However, the© cancer Jones cell & membrane Bartlett gainsLearning, LLC cell signals.158 While performingNOT theirFOR specialized SALE OR function, DISTRIBUTION these molecules due to ectopicNOT hormone FOR productionSALE OR and/ DISTRIBUTION the differentiated epithelial cells are flat. As the cells go or malignant changes specific to the tissue type. Outcomes through cell division, however, they become more rounded of this change enable the cancer to avoid immune surveil- and detach from the surrounding cells, although the mech- lance, promote invasion, and metastasize.1 anisms responsible© Jones for & this Bartlett change inLearning, shape remain LLC unclear. Cells have© aJones skeleton & with Bartlett interior Learning, and exterior LLC func- Recently aNOT protocadherin, FOR SALE PCDH7, OR DISTRIBUTION has been implicated tions dependentNOT upon FOR the SALEmakeup OR of the DISTRIBUTION protein filaments. in the typical “rounding” of the cell at the beginning of The shape and mechanical strength of the cell; its ability mitosis. Research suggests that this biomarker may have to grow, divide, direct, and support the signaling network; potential as an anti-mitotic chemotherapy.159 Because most and its ability to be mobile are all supported by the func cancer cells are constantly in some phase of cell division, tions of the cytoskeleton. The internal function of the cyto- © Jonesit is possible & Bartlett that the Learning, loss of adhesion LLC and rounding of the © Jonesskeleton & permits Bartlett substances Learning, to move LLC within the cell. On the NOT cellsFOR might SALE enhance OR DISTRIBUTION their metastatic capability. Mutated NOTexterior FOR membrane, SALE OR mi DISTRIBUTIONcrotubules evoke a rigidity to add CDH1, which codes for E-cadherin, is associated with strength to the membrane surface. Internally, they promote gastric and lobular breast cancers. Other genes associated movement of organelles within the cytoplasm. with contact inhibition include Merlin, LATS2, and YAP. When malignancy is manifested, the cell loses exter- Merlin is a tumor suppressor gene located in the nucleus; nal cytoskeleton control. Consequently, the cell may lose © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC when mutated, it is associated with development of neuro- rigidity, round up, and be more amenable to continued cel- fibromatosis 2 NF2( ). TheNOT mutated FOR forms SALE of LATS2 OR DISTRIBUTION and lular division. Multiple proteinNOT types FOR participate SALE inOR these DISTRIBUTION YAP are associated with mesotheliomas and hepatocellular changes associated with malignant transformation and carcinomas, respectively.160–163 locomotion.165

The normal cell condition can be assessed through the Though not a hallmark themselves, a variety of signaling electrical properties of the cell membrane. As the malig- pathways can be correlated with one or more of the major nant cell becomes transformed, the membrane gains more characteristics of cancer. Much like the “motherboard” © Jonesphospholipids, & Bartlett especially Learning, anions, LLC than are found in normal © Jonesthat contains & Bartlett the circuitry Learning, of a computer LLC and directs the NOT cells,FOR causing SALE the OR plasma DISTRIBUTION membrane to have a more negative NOTmultiple FOR SALEpathways OR and DISTRIBUTION branching trails, the signaling

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18 PART I The Cancer Problem

networks of the cell direct the mechanisms that regulate characteristic, causing the tumor to adapt and shift from © Jonesthe & Bartlettbiology of Learning, the normal LLCcell. If the normal circuitry© is Jones dependence & Bartlett on angiogenesisLearning, toLLC increased activity of some NOT FORknown, SALE then OR the DISTRIBUTION molecular networks that are altered dueNOT FORother SALE characteristic OR DISTRIBUTION such as invasiveness and metastasis. to malignancy could be inhibited, causing an “error” in The fact that the antiangiogenesis treatments have had the circuitry. Because therapeutic agents are directed at transitory effects demonstrates the innate ability of the one target in the pathway, the side effects and nonspecific malignant cell to utilize mechanisms that enable survival toxicities are less frequent than the generalized toxicities skills.166 The hypoxic cancer cells induced by antiangio- seen with chemotherapeutic© Jones or radiation & Bartlett results. Learning,1 As seen LLCgenic inhibitors may invade© Jones the nearby & Bartlett tissues Learning, in their LLC in Figure 1-3 and FigureNOT 1-4 FOR, the SALE hallmark OR capabilities DISTRIBUTION quest for access to vascularizedNOT FOR tissue. SALE167 ThisOR DISTRIBUTION mecha- have redundant and overlapping signaling pathways; thus, nism has been validated in glioblastomas but not in other even if a targeting agent inhibits one circuit, it may not tumors.168 block the entire pathway, allowing the cancer cell to sur- The reprogrammed signaling networks of the cancer cell vive with© Jones remaining & Bartlett function(s) Learning, awaiting LLCadaptation of enable its© survival. Jones Figure& Bartlett 1-3 depicts Learning, the four LLC circuits— the progeny.1 As noted previously, this adaptation can be motility, cytostasis and differentiation, proliferation, and NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION accomplished by “mutation, epigenetic reprogramming, viability—involved in this process. Though the figure dra- or remodeling of the stromal microenvironment.”1(p667) matically simplifies matters, note the crosstalk between cir- By targeting angiogenesis, some of the angiogenetic inhib- cuits within one cell; this crosstalk also occurs with other itors have been successful in suppressing this hallmark cancer cells within the microenvironment of the tumor.1 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Motility Circuits Cytostasis and Differentiation © Jones & Bartlett Learning, LLC © Jones Circuits& Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALEanti-growth OR DISTRIBUTION proteases factors Apc

adjacent cells E-cadherin b-catenin TCF4 p16

extracellular integrins cyclin D © Jonesmatrix & Bartlett Learning, LLC © Jones & Bartlett Learning,Smads LLC NOT FOR SALE OR DISTRIBUTION NOTpRb FOR SALE OR DISTRIBUTION Proliferation E2F Circuits p21 receptor growth tyrosine Ras DNA-damage changes hallmark sensor factors kinases in gene capabilities © Jones & Bartlett Learning, LLC © MycJones & Bartlettexpression Learning, LLCp53 NOT FOR SALE ORhormones DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

survival factors© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Bcl-2 death abnormality factors sensor © Jones & Bartlett Learning,cytokines LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Viability Circuits

FIGURE 1-3

© Jones & BartlettIntracellular Learning, signaling LLC network for regulation of cancer© Jones cell operations. & Bartlett Learning, LLC NOT FOR SALESource: OR Reproduced DISTRIBUTION from Hanahan and Weinberg.1 NOT FOR SALE OR DISTRIBUTION

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CHAPTER 1 Biology of Cancer 19

EGFR Cyclin-dependent © Jones & Bartlett Learning, LLC inhibitors © Joneskinase & inhibitors Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Sustaining Evading Aerobic glycolysis Immune activating proliferative growth inhibitors anti-CTLA4 mAb signaling suppressors

Proapoptotic Resisting Enabling Telomerase © JonesBH3 mimetics & Bartlett Learning,cell LLC © Jonesreplicative & BartlettInhibitors Learning, LLC NOT FOR SALE ORdeath DISTRIBUTION NOTimmortality FOR SALE OR DISTRIBUTION

Genome Tumor- instability & promoting © Jones & Bartlett Learning, LLC mutation © Jones & Bartlettinflammation Learning, LLC NOT FOR SALE OR DISTRIBUTIONPARP Inducing NOTActivating FOR SALE OR DISTRIBUTIONSelective anti- inhibitors angiogenesis invasion & inflammatory drugs metastasis

FIGURE 1-4

Targeted treatments directed at cancer hallmarks. ©Source: Jones Reproduced & Bartlettfrom Hanahan Learning, and Weinberg.1 LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION MOTILITY CIRCUITS in this case) of cellular growth and proliferation.171 The nuclear p16 gene (INK4a) is a cyclin-dependent kinase Extracellular and transcellular signaling for the motility cir- inhibitor 2A (CDKN2A) tumor suppressor gene that nor- © Jonescuitry & occurs Bartlett via intramembraneLearning, LLC receptors (proteases) and © Jonesmally monitors & Bartlett cellular Learning, division and LLC proliferation.62 pRB1 NOT paracrineFOR SALE overproduction, OR DISTRIBUTION as these enzymes and hormones NOTis aFOR retinoblastoma SALE OR gene DISTRIBUTION protein with multiple actions, are transported across the cellular membrane. The APC including (1) action as a tumor suppressor to regulate cell (activated protein C) receptor influences the innate immune growth, (2) inhibition of DNA replication, (3) interaction response by decreasing the population of natural killer and with other proteins to promote apoptosis, and (4) promo- Th17 (T-helper cells).169 Other proteases affect E-cadherin 172 © Jones & Bartlett Learning,tion LLC of cellular differentiation.© Jones The E2F & proteinBartlett is a Learning,tran- LLC and the extracellular–intracellular matrix, leading to stimula- scription factor that affects gene expression and ultimately tion of the intracellular integrinsNOT associated FOR SALE with breakdownOR DISTRIBUTION changes in gene expression.172,173NOT If anyFOR of SALEthese molecules OR DISTRIBUTION of the matrix of the cellular infrastructure. Nuclear transcrip- are mutated, the results will be altered gene expression and tion factor 4 stimulates the tumor suppressor gene (TCF4), the possibility of a transformed cell. Finally, the nuclear p21 with direct signaling to other nuclear genes and indirect sig- (also known as the HRAS oncogene) receives signals from naling to cMyc© Jones affecting & Bartlettchanges in Learning, gene expression. LLC1,170 the intracellular© Jones Smad genes & Bartlett to regulate Learning, cell division; LLC these NOT FOR SALE OR DISTRIBUTION signals simplyNOT direct FOR cell growth SALE or OR division. DISTRIBUTION173 CYTOSTASIS AND DIFFERENTIATION CIRCUITS PROLIFERATION CIRCUITS Transforming growth factor beta (TGF-β) has transmem- © Jonesbrane & receptors Bartlett that Learning, signal an LLCintracellular gene family, © JonesThe receptor & Bartlett tyrosine Learning, kinases promote LLC proliferation through NOT SmadFOR, toSALE produce OR proteins DISTRIBUTION for regulation (or dysregulation, NOTmultiple FOR signalingSALE OR pathways DISTRIBUTION and are also described in the

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20 PART I The Cancer Problem

section “Hallmark: Deregulated Growth and Mitogenesis.” transcriptomes, proteomes, and epigenomes, among others. © JonesWhen & Bartlett activated, Learning, the RTKs LLC can activate the Ras family© of Jones The & analysisBartlett of theseLearning, data has LLC made overwhelming quanti- NOT FORoncogenes SALE ORand ultimatelyDISTRIBUTION Myc oncogenes. The Myc oncoNOT- FORties of SALE “interactome” OR DISTRIBUTION information available and led to better gene participates in cell-cycle progression as part of the pro- understanding of cancer biology and its treatment with inno- liferation circuitry. When this gene develops mutations, it vative targeted therapies for sustained remissions or cure.3 acts to prevent apoptosis and promote cellular transforma- The amount of data available to answer the questions of tion. Overexpression of the mutated Myc gene is frequently how cancer begins and transforms into an aggressive tumor associated with hematopoietic© Jones tumors. & Bartlett58,60,173 Learning, LLCwith far-reaching metastatic© Jones processes & Bartlettsuggests numerous Learning, LLC Importantly, all of NOTthe circuits FOR mergeSALE to OR effect DISTRIBUTION changes possibilities for final answers.NOT FORHowever, SALE with OR the DISTRIBUTIONexplora- in gene expression, which then affect all of the hallmark tion of these enormous data sets, it has also become obvious capabilities. Integral to this collection of circuits is the that each tumor reveals only some of its personal genetics DNA damage sensor, TP53 (tumor protein p53) tumor and secrets to the subpopulations of cells, thereby yielding suppressor© Jones gene, which& Bartlett is known Learning, as the “guardian LLC of the varying phenotypes© Jones &as Bartlettthe stages Learning,of the tumor LLC evolve. The genome.” It is located in the nucleus of cells and binds final answers to the questions about the biology of cancer NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION directly to DNA when damage there needs to be repaired, will emerge only as understanding is created from the large or signals for apoptosis when unrepairable DNA damage is data sets that are enabled to “chat among themselves” as identified.174 new details are combined, condensed, and manipulated to yield new outcomes of knowledge to be anticipated in the © Jones & Bartlett Learning, LLC © Jonesfuture. & Bartlett3 Learning, LLC NOT FORVIABILITY SALE OR CIRCUITS DISTRIBUTION NOT FORThis SALE chapter OR DISTRIBUTIONhas identified and described some of the new data that reveal complex relationships between The viability circuits mediate the death and survival factors genes, signaling pathways, and characteristics of malig- associated with the cell mechanisms. Survival factors have nant cells. Models for the development of cancer were receptors on the cell membrane. Once activated through also described. The “hallmarks of cancer” can serve as a phosphorylation, they ©have Jones the ability & Bartlett to limit Learning, cell death, LLCguide through the complex© Jones mechanisms & Bartlett and interactions Learning, LLC facilitate angiogenesis, NOTresist apoptosis,FOR SALE deplete OR the DISTRIBUTION immune of the malignant cell asNOT it attempts FOR SALEto survive. OR1,17 DISTRIBUTION Even response, and produce extracellular matrix–modifying specific characteristics of the malignant cell incorporate enzymes to promote invasion and metastasis with wide dis- elements from other hallmarks, however. The ultimate semination.1,175 One example, the BCL2 gene product, is goal is to clarify complex concepts into simple expla- a mitochondrial© Jones &membrane Bartlett protein Learning, that blocks LLC apoptosis nations ©so Jonesthat cancer & Bartlett nurses can Learning, develop or LLC update an 176 in cellsNOT such FORas lymphocytes. SALE OR DeathDISTRIBUTION factors are also acti- understandingNOT FOR of the SALEbiology OR of cancer, DISTRIBUTION including sugges- vated by transmembrane receptors and include HIF-α and tions of rationale for the diagnosis and targeted treatment other factors that signal core metabolic pathways driven by of various cancer types. oncogenes or tumor suppressor genes to activate the expression of inflammation-related pathways.177 © Jones & Bartlett Learning, LLC © JonesREFERENCES & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 1. Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. CONCLUSION Cell. 2011;144:646-674. 2. Beamer LC, Linder L, Eggert J. The impact of genomics on oncology The biology of cancer is sometimes viewed as a multifaceted nursing. Nurs Clin North Am. 2013;48(4):585-626. association of simultaneous processes “gone wrong” within 3. Weinberg R. Coming full circle: from endless complexity to simplicity © Jones & Bartlett Learning, LLC and back again. Cell. 2014;157:267-271.© Jones & Bartlett Learning, LLC the cell. Figure 1-4 suggests targeted therapies. This chapter NOT FOR SALE OR DISTRIBUTION4. Marjanovic N, Weinberg R,NOT Chaffer FOR C. Cell SALE plasticity ORand heterogeneDISTRIBUTION- has suggested additional hallmarks based on the literature ity in cancer. Clin Chem. 2013;59(1):168-179. 14 and noted other changes as enablers or drivers. Research is 5. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in currently examining these factors to determine if a targeted cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822-829. therapy might be able to directly affect a specific malignant 6. Ward P, Thompson C. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21:297-308. change© inJones a tumor. & Bartlett Learning, LLC 7. Calabrese© Jones C, Poppleton & BartlettH, Kocak M, Learning, et al. A perivascular LLC niche for SinceNOT 2000, FOR the SALE complexity OR DISTRIBUTIONof the evolution of cancer brain NOTtumor stem FOR cells. SALE Cancer Cell. OR 2007; DISTRIBUTION 11(1):69-82. has been visualized as an even more remarkably detailed 8. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat process as a result of the generation of large data sets able Rev Cancer. 2009;9:285-289. to absorb multiple entities at a time—indeed, thousands 9. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571-573. of entities simultaneously.1,17 By studying the elements of © Jones & Bartlett Learning, LLC © Jones10. &Nati Bartlettonal Human Learning, Genome Research LLC Institute. Genetic variation pro- DNA, researchers have been able to describe not only the gram overview. January 15, 2015. http://www.genome.gov/10001551. NOT FORgenome, SALE but OR also DISTRIBUTION many other “omes”—for example, exomes,NOT FORAccessed SALE February OR DISTRIBUTION15, 2016.

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11. Nicolini C, Kendall F, Giaretti W. Objective identification of cell 38. Ho AS, Turcan S, Chan TA. Epigenetic therapy: use of agents target- cycle phases and subphases by automated image analysis. Biophys J. ing deacetylation and methylation in cancer management. Onco Targets © Jones1977;19(2):163-176. & Bartlett Learning, LLC © JonesTher. 2013;6:223-232.& Bartlett Learning, LLC NOT 12.FOR Cou ssensSALE LM, OR Werb DISTRIBUTION Z. Inflammation and cancer. Nature. NOT39. FORRodriguez-Paredes SALE OR M, EstellerDISTRIBUTION M. Cancer epigenetics reaches main- 2002;420(6917):860-867. stream oncology. Nat Med. 2011;17(3):330-339. 13. Kawanishi S, Hiraku Y, Pinlaor S, Ma N. Oxidative and nitra- 40. Hojfeldt JW, Agger K, Heliin K. Histone lysine demethylases as targets tive DNA damage in animals and patients with inflammatory dis- for anticancer therapy. Nat Rev Drug Discovery. 2013;12:917-930. eases in relation to inflammation-related carcinogenesis. Biol Chem. 41. Laird PW. Cancer epigenetics. Hum Mol Genet. 2005;14(1):R65–R76. 2006;387:365-372. © Jones & Bartlett Learning,42. LLC Baylin SB, Esteller M, Rountree ©MR, Jones et al. Aberrant & Bartlett patterns of Learning,DNA LLC 14. Giancotti FG. Deregulation of cell signaling in cancer. FEBS Lett. methylation, chromatin formation and gene expression in cancer. Hum 2014;588(16):2558-2570. NOT FOR SALE OR DISTRIBUTIONMol Genet. 2001;10:687-692. NOT FOR SALE OR DISTRIBUTION 15. Hanahan D, Coussens LM. Accessories to the crime: functions 43. Loeb LA. Human cancers express mutator phenotypes: origin, conse- of cells recruited to the tumor microenvironment. Cancer Cell. quences and targeting. Nat Cancer. 2011;11:450-457. 2012;21:309-322. 44. American Cancer Society. Oncogenes and tumor suppressor genes. 16. Allegra A, Alonci A, Penna G, et al. The cancer stem cell hypothesis: a 2014. http://www.cancer.org/cancer/cancercauses/geneticsandcancer/ guide to ©molecular Jones targets. & BartlettCancer Invest .Learning, 2014;32:470-495. LLC genesandcancer/genes-and-cancer-oncogenes-tumor-suppressor-genes© Jones & Bartlett Learning, LLC 17. HanahanNOT D, Weinberg FOR R. TheSALE hallmarks OR of DISTRIBUTIONcancer. Cell. 2000;100:57-70. Accessed FebruaryNOT 15,FOR 2016 SALE OR DISTRIBUTION 18. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. 45. Levine A, Hu W, Feng Z. Tumor suppressor genes. In: Mendelsohn J, Nat Med. 2004;10(8):789-799. Howley PM, Israel MA, Gray JW, Thompson CB, eds. The Molecular 19. Crick F. Central dogma of molecular biology. Nature. 1970;227:561-563. Basis of Cancer. 3rd ed. Philadelphia: Elsevier Saunders; 2008:31-38. 20. Ghildiyal M, Zamore P. Small silencing RNAs: an expanding universe. 46. Harris TJR, McCormick F. The molecular pathology of cancer. Nat Rev Nat Rev Genet. 2009;10(2):94-108. Clin Oncol. 2010;7:251-265. © Jones21. Rit &chier Bartlett W, Gao D, Learning, Rasko J. Defining LLC and providing robust controls for © Jones47. Geneti &cs BartlettHome Reference. Learning, PTEN. February LLC 2016. http://ghr.nlm.nih NOT FORmicroRNA. SALE Bioinformatics OR DISTRIBUTION Adv Access. 2012;28(38):2058-2061. NOT FOR.gov/gene/PTEN. SALE ORAccessed DISTRIBUTION February 15, 2016. 22. Siomi MC, Sato K, Pezic D, Aravin AA. PIWI-interacting small 48. Online Mendelian Inheritance in Man. Phosphatase and tensin homo- RNAs: the vanguard of genome defense. Nat Rev Mol Cell Biol. log; PTEN. January 19, 2016. http://www.omim.org/entry/601728. 2011;12:246-258. Accessed February 15, 2016. 23. Whitehead KA, Dahlman, JE, Langer RS, Anderson, DG. Silencing or 49. Pezzolesi MG, Zbuk KM, Waite KA, Eng C. Comparative genomic stimulation? SiRNA delivery and© Jonesthe immune & system. Bartlett Annu RevLearning, Chem LLCand functional analyses reveal a novel© Jones cis-acting & PTEN Bartlett regulatory Learning, ele- LLC Biomol Eng.2011;2:77-96. ment as a highly conserved functional E-box motif deleted in Cowden 24. Wang Z, Rao DD, Senzer N, NemunaitisNOT FOR J. RNA SALE interference OR and DISTRIBUTION can- syndrome. Hum Mol Genet. 2007;16:1058-1071.NOT FOR SALE OR DISTRIBUTION cer therapy. Pharma Res. 2011;28(12):2983-2995. 50. Peltier J, O’Neill A, Schaffer DV. PI3K/Akt and CREB regulate adult 25. Genetics Home Reference. Germline. February 8, 2016. http://ghr.nlm neural hippocampal progenitor proliferation and differentiation.Dev .nih.gov/glossary=germline. Accessed February 15, 2016. Neurobiol. 2007;67(10):1348-1361. 26. Genetics Home Reference. Somatic cell. February 8, 2016. http://ghr 51. Rafalski VA, Brunet A. Energy metabolism in adult neural stem cell .nlm.nih.gov/glossary© Jones= &somaticcell. Bartlett Accessed Learning, February 15, LLC 2016. fate. Prog Neurobiol.© Jones 2011;93(2):182-203. & Bartlett Learning, LLC 27. Genetics Home Reference. Oncogene. February 8, 2016. http://ghr.nlm 52. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. .nih.gov/glossaryNOT FOR=oncogene. SALE Accessed OR February DISTRIBUTION 15, 2016. 2004;18(16):1926-1945.NOT FOR SALE OR DISTRIBUTION 28. Genetics Home Reference. Tumor suppressor gene. February 8, 2016. http:// 53. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in ghr.nlm.nih.gov/glossary=tumorsuppressorgene. Accessed February 15, human cancer. Int J Mol Sci. 2012;13(12):1886-1918. 2016. 54. Genetics Home Reference. EGFR. February 8, 2016. http://ghr.nlm.nih 29. Lahtz CL, Pfeiffer GP. Epigenetic changes of DNA repair genes in can- .gov/gene/EGFR. Accessed February 15, 2016. © Jonescer. & J MolBartlett Cell Biol. Learning, 2011;3:51-58. LLC © Jones55. Online & Mendelian Bartlett Inheritance Learning, in Man. EpidermalLLC growth factor recep- NOT 30.FOR Stratton SALE MR, ORCampbell DISTRIBUTION PJ, Futreal PA. The cancer genome. Nature. NOT FORtor; EGFR SALE. http://omim.org/entry/131550?search OR DISTRIBUTION=EGFR&highlight= 2009;458:719-724. egfr. 2015. Accessed February 15, 2016. 31. Merid SK, Goranskaya D, Alexeyenko A. Distinguishing between 56. Genetics Home Reference. BRAF. February 8, 2016. http://ghr.nlm.nih. driver and passenger mutations in individual cancer genomes by net- gov/gene/BRAF. Accessed February 15, 2016. work enrichment analysis. BMC Bioinformatics. 2014;15:308-329. 57. Online Mendelian Inheritance in Man. V-raf murine sarcoma viral 32. Lee MJ, Ye AS, Gardino AK, et al. Sequential application of anticancer oncogene homolog B1; BRAF. November 30, 2015. http://omim.org/ drugs enhances cell death by© rewiring Jones apoptotic & Bartlett signaling networksLearning,. LLCentry/164757. Accessed February ©15, Jones2016. & Bartlett Learning, LLC Cell. 2012;149(4):780-794. NOT FOR SALE OR DISTRIBUTION58. Genetics Home Reference. KRAS. FebruaryNOT FOR 8, 2016. SALE http://ghr.nlm.nih OR DISTRIBUTION 33. Christmann M., Tomicic MT, Roos WP, Kaina B. Mechanisms of .gov/gene/KRAS. Accessed February 15, 2015. human DNA repair: an update. Toxicology. 2003;193:3-34. 59. Online Mendelian Inheritance in Man. V-ki-ras2 Kirsten rat sarcoma 34. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanisms to viral oncogene homolog; KRAS. November 30, 2015. http://omim.org/ therapy. Cell. 2012;150:12-27. entry/190070. Accessed February 15, 2016. 35. de Lartige,© J.Jones Targeting & epigenetics Bartlett for cancerLearning, therapy: scores LLC of agents 60. Genetics Home© JonesReference. MYC& Bartlett. February 8,Learning, 2016. http://ghr.nlm.nih LLC capture interest of researchers. OncLive. 2013. http://www.onclive.com/ .gov/gene/MYC. Accessed February 15, 2016. publications/Oncology-live/2013/october-2013/Targeting-Epigenetics-NOT FOR SALE OR DISTRIBUTION 61. Online MendelianNOT Inheritance FOR SALE in Man. V-myc OR avian DISTRIBUTION myelocytomasos viral for-Cancer-Therapy-Scores-of-Agents-Capture-Interest-of-Researchers. oncogene homolog; MYC. November 30, 2015. http://omim.org/entry/ Accessed May 3, 2016. 190080?search=myc&highlight=myc. Accessed December 1, 2015. 36. Tonna S, El-Osta A, Cooper ME, Tikellis C. Metabolic memory and 62. Genetics Home Reference. CDKN2A. February 8, 2016. http://ghr.nlm. diabetic nephropathy: potential role for epigenetic mechanisms. Nat nih.gov/gene/CDKN2A. Accessed February 15, 2016. © JonesRev & Nephrol. Bartlett 2010;6 Learning,:332-334. LLC © Jones63. Online & Mendelian Bartlett Inheritance Learning, in Man. Cyclin-dependentLLC kinase inhibi- 37. Ohtani K, Dimmeler S. Epigenetic regulation of cardiovascular differ- tor 2A; CDKN2A. November 30, 2015. http://omim.org/entry/600160. NOT FORentiation. SALE Cardiovasc OR DISTRIBUTIONRes. 2011;1:1-9. NOT FORAccessed SALE May 3, 2016.OR DISTRIBUTION

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64. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between 89. Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization tumor stroma generation and wound healing. N Engl J Med. 1986;315: via endothelial differentiation of glioblastoma stem-like cells. Nature. © Jones & 1650-1659.Bartlett Learning, LLC © Jones &2010;468:824-828. Bartlett Learning, LLC NOT FOR65. SALEDeNardo OR DG, DISTRIBUTIONAndreu P, Coussens LM. Interactions between lymNOT- FOR90. NatiSALEonal Cancer OR DISTRIBUTIONInstitute. Adult non-Hodgkin lymphoma treatment phocytes and myeloid cells regulate pro- versus anti-tumor immunity. (PDQ): Health professional version. 2014. http://www.cancer.gov/ Cancer Metastasis Rev. 2010;29:309-316. cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfessional/ 66. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and page3. Accessed May 3, 2016. cancer. Cell. 2010;140:883-899. 91. Schafer M, Werner S. Cancer as an overhealing wound: an old hypoth- 67. Qian BZ, Pollard JW. Macrophage© Jones diversity & Bartlett enhances tumorLearning, progres- LLC esis revisited. Nat Rev Mol© Cell Jones Biol. 2008;9:628-638. & Bartlett Learning, LLC sion and metastasis. Cell. 2010;141:39-51. 92. Coffelt SB, Lewis CE, Naldini L, Brown JM, et al. Elusive identities 68. Colotta F, Allavena P, SicaNOT A, Garlanda FOR C, SALE Mantovani OR A. Cancer-related DISTRIBUTION and overlapping phenotypesNOT of proangiogenic FOR SALE myeloid OR cells inDISTRIBUTION tumors. inflammation, the seventh hallmark of cancer: links to genetic instabil- Am J Pathol. 2010;176:1564-1576. ity. Carcinogenesis. 2009;30:1073-1081. 93. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues 69. Bellazzo A, Di Minin G, Collavin L. Cytoplasmic gain-of-function for that interface with the entire organism. Dev Cell. 2010;18:884-901. mutant p53 contributes to inflammation-associated cancer. Mol Cell 94. Johansson M, Denardo DG, Coussens LM. Polarized immune Oncol© . Jones2015;2:4. & Bartlett Learning, LLC responses© Jones differentially & Bartlett regulate cancer Learning, development. LLC Immunol Rev. 70. CooNOTks T, PaterasFOR IS,SALE Tarcic O,OR et DISTRIBUTIONal. Mutant p53 prolongs NF-κB 2008;222:145-154.NOT FOR SALE OR DISTRIBUTION activation and promotes chronic inflammation and inflammation- 95. Murdoch C, Muthana M, Coffelt SB, Lewis CE. Theory of myeloid associated colorectal cancer. Cancer Cell. 2013;23:634-646. cells in the promotion of tumor angiogenesis. Nat Rev Cancer. 71. Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;8:618-631. 2008;27:6245-6251. 96. De Palma M, Murdoch C, Venneri MA, Naldini L, Lewi CE. 72. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within Tie2-expressing monocytes: regulation of tumor angiogenesis and © Jones & tumorBartlett stroma Learning, promote breast LLC cancer metastasis. Nature. 2007;© Jones &therapeutic Bartlett implications. Learning, Trends LLCImmunol. 2007;28:519-524. NOT FOR SALE449:557-563. OR DISTRIBUTION NOT FOR97. YanSALEg L, Pang OR Y, MosesDISTRIBUTION HL. TGF-beta and immune cells: an impor- 73. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune tant regulatory axis in the tumor microenvironment and progression. system during cancer development. Nat Rev Cancer. 2006;6:24-37. Trends Immunol. 2010;31:220-227. 74. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat 98. Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction Rev Cancer. 2003;3(6):401-410. of lymphoid like stroma and immune escape by tumors that express 75. de Oliveira RL, Hamm ©A, MazzoneJones M. & Growing Bartlett tumor Learning, vessels: more LLC the chemokine CCL21. Science© Jones. 2010;328:749-752. & Bartlett Learning, LLC than one way to skin a cat: implications for angiogenesis targeted cancer 99. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson therapies. Mol Aspects MedNOT. 2011;32:71-87. FOR SALE OR DISTRIBUTIONCC. Regulatory T cells in NOTcancer. AdvFOR Cancer SALE Res. 2010;107:57-117. OR DISTRIBUTION 76. Jain RK. Normalization of tumor vasculature: an emerging concept in 100. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: link- antiangiogenic therapy. Science. 2005;307(5706):58-62. ing inflammation and cancer. J Immunol. 2009;182:4499-4506. 77. Fukumura D, Jain RK. Tumor microvasculature and microenviron- 101. Shay JW, Wright WE. Telomeres and telomerase in normal and cancer ment: targets for anti-angiogenesis and normalization. Microvasc Res. stem cells. FEBS Lett. 2010;58(17):3819-3825. 2007;74(2–3):72-84.© Jones & Bartlett Learning, LLC 102. Forrester© Jones W. The Ror& receptorBartlett tyrosine Learning, kinase family. CellLLC Mol Life Sci. 78. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective iden- 2002;59(1):83-96. tificationNOT ofFOR tumorigenic SALE breast OR cancer DISTRIBUTION cells. Proc Natl Acad Sci USA. 103. Imel NOTE, Econs, FOR M. Fibroblast SALE growth OR DISTRIBUTIONfactor 23: Roles in health and 2003;100:3983-3988. disease. JASN. 2005;16:2565-2575. 79. Cho RW, Clarke MF. Recent advances in cancer stem cells. Curr Opin 104. Sawada O, Kawamura H, Kakinoki M, Sawada T, Ohii M. Vascular Genet Dev. 2008;18:1-6. endothelial growth factor in the aqueous humour in eyes with 80. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an myopic choroidal neovascularization. Acta Ophthalmol. 2011;89(5): © Jones & emergingBartlett axis Learning,of evil in the war LLCon cancer. Oncogene. 2010;29:4741-4751.© Jones &459-462. Bartlett Learning, LLC NOT FOR81. SALEMani SA, OR Guo W,DISTRIBUTION Liao MJ, et al. The epithelial–mesenchymal transitionNOT FOR105. GreSALEen JL, ORKuntz DISTRIBUTION SG, Sternberg PW. Ror receptor tyrosine kinases: generates cells with properties of stem cells. Cell. 2008;133:704-715. orphans no more. Trends Cell Biol. 2008;18(11):536-544. 82. Morel AP, Lièvre M, Thomas C, et al. Generation of breast cancer 106. Marquard J, Eng C. GeneReviews: MEN2. http://www.ncbi.nlm.nih stem cells through epithelial-mesenchymal transition. PLoS One. .gov/bookshelf/br.fcgi?book=gene&part=men2. Accessed May 3, 2016. 2008;3:e2888. 107. Lemmon MA, Schlessinger J. Cell signaling by receptor-tyrosine 83. Brabletz T, Jung A, Spaderna S, et al. Opinion: migrating cancer stem kinases. Cell. 2010;141(7):1117-1134. cells: an integrated concept© Jonesof malignant & tumourBartlett progression. Learning, Nat Rev LLC108. Wilson TR, Fridly and J,© Yibing Jones Y, et al&. WidespreadBartlett potential Learning, for LLC Cancer. 2005;5:744-749.NOT FOR SALE OR DISTRIBUTIONgrowth-factor–driven resistanceNOT FORto anticancer SALE kinase OR inhibitors.DISTRIBUTION 84. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial– Nature. 2012;487:505-509. mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131-142 109. Warburg O. Über den Stoffwechsel der Carcinomzelle. Klin 85. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after con- Wochenschr. 1925;4;534-536. ventional therapy display mesenchymal as well as tumor-initiating fea- 110. Warburg D. On the origination of cancer cells. Science. tures.© JonesProc Natl Acad & Bartlett Sci USA. 2009;106:13820-13825. Learning, LLC 1956;123:309-314.© Jones & Bartlett Learning, LLC 86. Buck E, Eyzaguirre A, Barr S, et al. Loss of homotypic cell adhesion 111. Warburg D. On respiratory impairment in cancer cells. Science. by NOTepithelial–mesenchymal FOR SALE transitionOR DISTRIBUTION or mutation limits sensitiv- 1956;124:269-270.NOT FOR SALE OR DISTRIBUTION ity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 112. Vander Heiden MG, Cantley LC, Thompson CB. Understanding 2007;6:532-541. the Warburg effect: the metabolic requirements of cell proliferation. 87. Soda Y, Marumoto T, Friedmann-Morvinski D, et al. Transdifferentiation Science. 2009;324:1029-1033. of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci 113. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. © Jones & USABartlett. 2011; 108:4274-4280. Learning, LLC © Jones &Cell Bartlett 2008;134:703-707. Learning, LLC 88. El Hallani S, Boisselier B, Peglion F, et al. A new alternative mechanism 114. Koppenol WH, Bounds P, Dang CV. Otto Warburg’s contribu- NOT FOR SALEin glioblastoma OR DISTRIBUTION vascularization: tubular vasculogenic mimicry. BrainNOT. FOR tionsSALE to current OR DISTRIBUTIONconcepts of cancer metabolism. Nat Rev Cancer. 2010;133:973-982. 2011;11:325-335.

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115. Carvalho KC, Cunha IW, Rocha RM, et al. GLUT1 expression 140. Okada Y, Shimizu T, Maeno E, Tanabe S, Wang X, Takahashi N. in malignant tumors and its use as an immunodiagnostic marker. Volume-sensitive chloride channels involved in apoptotic volume © Jones Clinics& Bartlett. 2011;66(6):965-972. Learning, LLC © Jonesdecrease & Bartlett and cell death. Learning, J Membrane Biol LLC. 2006;209:21-29. NOT 116.FOR Kei SALElin D. The OR History DISTRIBUTION of Cell Respiration and Cytochrome.Cambridge, NOT141. FOR Bortner SALE CB, Cidlowski OR DISTRIBUTION JA. Ion channels and apoptosis in cancer. Phil UK: Cambridge University Press; 1966. Trans R Soc B. 2014;369(1638):1-9. 117. Racker E. Bioenergetics and the problem of tumor growth. Am Sci. 142. Kelly JL, Novak AJ, Fredericksen ZA, et al. Germline variation in 1972;60:56-63. apoptosis pathway genes and risk of non-Hodgkin’s lymphoma. 118. Cheung EC, Vousden KH. The role of p53 in glucose metabolism. Cancer Epidemiol Biomarkers Prev. 2010;19(11):2847-2858. Curr Opin Cell Biol. 2010;22(2):186-191.© Jones & Bartlett Learning,143. LLC Suganuma M, Saha A, Fujiki H.© New Jones cancer treatment & Bartlett strategy Learning, using LLC 119. Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic combination of green tea catechins and anticancer drugs. Cancer Sci. glycolysis in cancer cells. CancerNOT Res. FOR2004;64:3892-3899. SALE OR DISTRIBUTION2011;102(2):317-323. NOT FOR SALE OR DISTRIBUTION 120. Sonveaux P, Vegran F, Schroeder T, et al. Targeting lactate-fueled res- 144. Collado M, Serrano M. Senescence in tumors: evidence from mice piration selectively kills hypoxic tumor cells in mice. J Clin Invest. and humans. Nat Rev Cancer. 2010;10:51-57. 2008.;118:3930-3942. 145. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell 121. Bayley JP, Devilee P. Warburg tumors and the mechanisms of mito- strains. Exp Cell Res. 1961;25:585-621. chondrial© tumorJones suppressor & Bartlett genes: barking Learning, up the right LLC tree? Curr 146. Collado M,© Blasco Jones MA, Serrano& Bartlett M. Cellular Learning, senescence in cancerLLC and Opin GenetNOT Dev. FOR 2010;20:324-329. SALE OR DISTRIBUTION aging. Cell.NOT 2007;130:223-233. FOR SALE OR DISTRIBUTION 122. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis 147. Balk B, Maicher A, Dees M, et al. Telomeric RNA-DNA hybrids of human glioblastoma multiforme. Science. 2008;321:1807-1812. affect telomere-length dynamics and senescence. Nat Struc Mol Biol. 123. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate 2013;20:1199-1205. hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 148. Chen Z, Trotman LC, Shaffer D, et al. Crucial role of p53-depending 2006;25:4675-4682. cellular senescence in suppression of PTEN-deficient tumorigenesis. © Jones124. Rei& tmanBartlett ZJ, Yan Learning,H. Isocitrate dehydrogenase LLC 1 and 2 mutations in © JonesNature & . Bartlett2005;436:725-730. Learning, LLC NOT FORcancer: SALE alterations OR atDISTRIBUTION a crossroads of cellular metabolism. J Natl Cancer NOT149. FOR Nard ellaSALE C, Clohessy OR JG,DISTRIBUTION Alimonti AK, Paolo P. Pro-senescence ther- Inst. 2010;102:932-941. apy for cancer treatment. Nat Rev Cancer. 2011;11:503-511. 125. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabo- 150. Poliseno L, Pitto L, Simili M, et al. The proto-oncogeneLRF is under lite 2‑hydroxyglutarate accumulates in acute myelogenous leuke- post-transcriptional control of MiR-20a: implications for senescence. mia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. PLoS One. 2008;3:e2542. 2010;207:339-344. © Jones & Bartlett Learning,151. LLC Garzon R, Marcucci G, Croce ©CM. Jones Targeting & microRNAsBartlett in Learning, can- LLC 126. Figueroa ME, Abdel-Wahab O, Lu C, et al. 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FOR Canel SALEM, Serrels A,OR Frame DISTRIBUTION MC, Brunton VG. E-cadherin–integrin cross- recipe for cancer growth. Genes Dev. 2009;23:537. talk in cancer invasion and metastasis. J Cell Sci. 2013;126:393-401. 132. Dang CV, Lewis BC, Dolde C, Dang G, Shim H. Oncogenes in 158. Parsons SJ, Parsons JT. Src family kinases, key regulators of signal tumor metabolism, tumorigenesis and apoptosis. J Bioenergetics transduction. Oncogene. 2004;23:7906-7909. Biomembranes. 1997;29(4):345-354. 159. Ozlu N, Oureshi MH, Toyoda Y, et al. Quantitative comparison of a 133. Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory human cancer cell surface proteome between interphase and mitosis. mechanisms, and cellular response.© Jones Oncologist &. 2004;9(supplBartlett Learning,5):4-9. LLCEMBO J. 2014;34(2):251-265. © Jones & Bartlett Learning, LLC 134. Buzzai M, Jones RG, AmaravadiNOT RK, FOR et al. SystemicSALE treatment OR DISTRIBUTION with 160. 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167. Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways 172. Genetics Home Reference. RB1. February 2016. http://ghr.nlm.nih.gov/ of resistance and disease progression in response to antiangiogenic gene/RB1. Accessed February 15, 2016. © Jones & Bartletttherapy. Clin Learning, Cancer Res. 2009;15:5020-5025. LLC © Jones173. & Geneti Bartlettcs Home Learning,Reference. HRAS. LLC February 2016. http://ghr.nlm.nih NOT FOR168. SALE Norden ORAD, DISTRIBUTIONDrappatz J, Wen PY. Antiangiogenic therapiesNOT for FOR .gov/gene/HRAS.SALE OR DISTRIBUTION Accessed February 15, 2016. high-grade glioma. Nat Rev Neurol. 2009;5:610-620. 174. Genetics Home Reference. TP53. February 2016. http://ghr.nlm.nih 169. Azzazene D, Al Thawadi H, Al Farsi H, et al. Plasma endothelial pro- .gov/gene/TP53. Accessed February 15, 2016. tein C receptor influences innate immune response in ovarian cancer 175. Polyak K, Weinberg RA. Transitions between epithelial and mesen- by decreasing the population of natural killer and TH17 helper cells. chymal states: acquisition of malignant and stem cell traits. Nat Rev Int J Oncol. 2013;43(4):1011-1018.© Jones & Bartlett Learning, LLC Cancer. 2009;9:265-273. © Jones & Bartlett Learning, LLC 170. Yang X, Han H, De Carvalho D, et al. Gene body methylation can 176. Genetics Home Reference. BCL2. February 8, 2016. http://ghr.nlm.nih alter gene expression andNOT is a therapeutic FOR SALE target in cancer.OR DISTRIBUTION Cancer Cell. .gov/gene/BCL2. AccessedNOT February FOR 15, 2016. SALE OR DISTRIBUTION 2014;26:1-14. 177. Mantovani A, Allavena P, Sica A, Balkwill. Cancer-related inflamma- 171. Genetics Home Reference. SMAD gene family. 2016. http://ghr.nlm.nih tion. Nature. 2008;454:436-444. .gov/geneFamily/smad. Accessed February 15, 2016. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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