DOCSLIB.ORG

Intra-Tumor Heterogeneity of Cancer Cells and Its Implications for Cancer Treatment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intra-Tumor Heterogeneity of Cancer Cells and Its Implications for Cancer Treatment npg Acta Pharmacologica Sinica (2015) 36: 1219–1227 www.nature.com/aps Review Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment Xiao-xiao SUN, Qiang YU* Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or through- out different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phe- nomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effec- tive therapeutic strategies. Key words cancer cells; intra-tumor heterogeneity; genetic heterogeneity; signal transduction; cancer therapy Acta Pharmacologica Sinica (2015) 36: 1219–1227; doi: 10.1038/aps.2015.92; published online 21 Sep 2015 Introduction improve the understanding and management of this heteroge- Solid tumors are heterogeneous neoplasms composed of dif- neity in cancer treatment. ferent types of cells, including cancer cells as well as mesen- chymal cells, endovascular cells, and immune cells[1]. In addi- Heterogeneity in genetic mutation tion to the complex tissue architecture of a tumor, cancer cells Genomic aberrations in cancers have been recognized for a within a single tumor are also heterogeneous in their molecu- long time; these include base-pair substitutions, focal dele- lar signatures; this is referred to as intra-tumor heterogene- tions/amplifications, tandem duplications, chromosomal rear- ity[2-4]. These cell-to-cell variations in genetic signature, gene rangements and whole-genome duplications[7]. Recent studies expression, and post-translational modifications are recog- further revealed extensive variations in genomic aberrations nized in almost every type of cancer (Table 1). However, cur- within tumors. For example, in glioblastomas (GBMs), the rent therapies treat cancer as a homogenous disease. Targeted copy number variation of two commonly amplified receptor drugs have been developed against single or multiple aber- tyrosine kinases (RTKs), EGFR and PDGFRA, was identified rant molecular signatures based on the diagnosis of the mixed among cells from the same tumor specimen using multicolor populations of cancer cells, in most cases based on a single fluorescent in situ hybridization (FISH) mapping[8, 9]. More- biopsy[5, 6]. Thus, it is not surprising that drug resistance, both over, the majority of the cells had a mutual exclusive amplifi- intrinsic and adaptive, occur extensively in all types of cancer. cation of these two genes, whereas co-amplification was only Understanding the specific driving forces behind different observed in a minority of the cancer cells. There also seemed subtypes of intra-tumor heterogeneity will facilitate a better to be a spatial distribution of the differential gene amplifica- understanding of the nature of cancer, and will provide insight tions, with one or the other type of gene predominating in cer- into the development of more effective cancer therapies. tain areas of the same specimen. In particular, the PDGFRA- In this review, we summarize the evidence for both genetic amplified cells tended to be present close to the endothelial and non-genetic heterogeneity within a tumor, and focus cells. Similar intra-tumor heterogeneous genetic alterations on the possible origins and their impact on drug resistance. were also observed in other types of cancers. Gerlinger et al Finally, we discuss the strategies that could be adopted to performed whole-exome sequencing on DNA extracted from multiple regions of tumor samples obtained from one clear- cell renal cell carcinoma (ccRCC) patient[10]. Nine primary- * To whom correspondence should be addressed. E-mail [email protected] tumor regions of the nephrectomy specimen and two regions Received 2015-08-12 Accepted 2015-09-06 of the excised chest-wall metastasis were analyzed. Among all npg www.nature.com/aps Sun XX et al 1220 Table 1. Intra-tumor heterogeneity in different cancer types. Cancer type Types of heterogeneity Reference(s) Brain Mutations, amplifications and expressions of genes related to oncogenic signaling, proliferation, [8, 9, 18, 31, 33, 40] immune response and hypoxia, CD133 expression Renal Mutations, chromosome aberrations, DNA ploidy [10] Breast Cell surface marker expressions, genotypic alterations [11-13, 16, 41, 42] Leukemia Expressions of multiple cell surface markers, Ki-67, Bcl-2, cyclin D, cyclin E and RAS, [14, 23-28, 30, 35-37] phosphorylations of signaling proteins Colorectal CD133 and receptor tyrosine kinase expressions, phosphorylations of signaling proteins [19, 20, 34, 43] Melanoma Expressions of multiple cell surface markers and cytoplasmic proteins [21, 22, 44, 45] Lung DNA ploidy, EGFR and BRAF V600E mutations, p53, c-Myc and Ki-67 expressions, phosphorylations of [29, 31, 38, 46] signaling proteins Sarcoma O-glycosylation of MT1-MMP [39] Head and neck Genotypic alterations [47] of the nonsynonymous point mutations, insertions, and dele- profiles of approximately 6000 genes in 430 cells were quan- tions that changed the protein amino acid sequences, approxi- titatively analyzed. Although the gene expression profiles mately 31% of the mutations were ubiquitous across every of individual cells from the same tumor were more similar tumor region, 46% were shared by several but not all regions, to each other than those from different tumors, variable gene and 22% were present only in a single region. In breast can- expression between individual cells from the same tumor was cers, spatial and temporal intra-tumor heterogeneity have also common. According to this study, cell-to-cell variability been observed using comparative genomic hybridization and was evident in genes related to multiple cellular functions, FISH mapping[11, 12]. A recent genome-wide sequencing study including oncogenic signaling, proliferation, and the immune of 21 breast cancers has shown that although every tumor has and hypoxia responses. In particular, RTKs such as EGFR, a dominant subclonal lineage of tumor cells, subclonal diversi- PDGFRA, FGFR1 and their ligands, which are important fication was prominent in every tumor, and most of the muta- therapeutic targets, were expressed in a mosaic fashion. More- tions were found in just a fraction of the cells[13]. over, the splicing patterns of the mRNAs of these genes were Integrative analysis of all these genetic changes in a single also variable. For example, in one GBM sample, 7% of cells cancer and in-depth evaluation of the topographical infor- expressed wild-type EGFR, 19% expressed EGFRvIII, which mation, especially the function of this variation will greatly is an oncogenic mutant form with a deletion of exon 2–7, and enhance our understanding on cancer heterogeneity and 25% expressed EGFR del4, which is another oncogenic variant inform its use in cancer treatment. with a deletion of exon 4. In addition, 1% to 2% of cells co- expressed both wild-type EGFR and the EGFRvIII variant. Heterogeneity in gene expression In addition to genetic alterations, intra-tumor heterogeneity is Heterogeneity in protein modification also common in gene expression. The clusters of differentia- Differential posttranslational modifications of proteins have tion (CD) antigens were among the first and are the most fre- also been found in different cancer cells from the same tumor. quently identified proteins that are heterogeneously expressed A pioneer study of three well-characterized subpopulations within a tumor. For example, differential expression of CD34/ of colorectal carcinoma (CRC) cells that were isolated from CD38 in acute myeloid leukemia (AML) cells[14, 15], CD24/CD44 a single primary colon cancer has revealed a great degree of in breast cancer cells[16, 17], CD133 in colon cancers and brain heterogeneity in phosphorylation modifications of cytosolic tumors[18-20], and CD271 in melanoma cells[21, 22] have been fre- and membrane proteins, and a mechanism beyond differential quently found in patient samples. The so-called cancer hall- gene expression has been demonstrated[34]. Since then, het- mark genes, such as c-KIT[23], cyclins[24, 25], Ki67[25], Bcl-2[26-28], erogeneous modifications of multiple signaling proteins have c-Myc[29], RAS[30] and EGFR[31, 32] have also been frequently been identified, including STAT, ERK, p38, GSK3β, β-catenin, found to be differentially expressed within a single tumor. NF-κB, AKT, PTEN, S6 and Src family kinases[28, 35-38]. In addi- With the advances in deep-sequencing technology, the tion, intra-tumor heterogeneity in O-glycosylation has also examination of single-cell gene expression profiles has become been reported[39]. popular. In a large-scale study, full-length transcriptomes of 672 cells from five freshly resected human GBMs were gener- The origins of intra-tumor heterogeneity ated using SMART-seq (switching mechanism at the 5′ end of Intrinsic factors the RNA template sequencing) technology (96–192 cells per The various types of intra-tumor heterogeneity are generated tumor)[33]. After depleting the infiltrating immune cells as well by different mechanisms, which can be categorized as cell- as genes
Load more

Recommended publications
  • Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution Ravi G
    Published OnlineFirst June 8, 2017; DOI: 10.1158/1541-7786.MCR-17-0070 Review Molecular Cancer Research Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution Ravi G. Gupta and Robert A. Somer Abstract High-throughput genomic technologies have revealed a full mutational landscape of tumors could help reconstruct remarkably complex portrait of intratumor heterogeneity in their phylogenetic trees and trace the subclonal origins of cancer and have shown that tumors evolve through a reiterative therapeutic resistance, relapsed disease, and distant metastases, process of genetic diversification and clonal selection. This the major causes of cancer-related mortality. Real-time assess- discovery has challenged the classical paradigm of clonal ment of the tumor subclonal architecture, however, remains dominance and brought attention to subclonal tumor cell limited by the high rate of errors produced by most genome- populations that contribute to the cancer phenotype. Dynamic wide sequencing methods as well as the practical difficulties evolutionary models may explain how these populations grow associated with serial tumor genotyping in patients. This review within the ecosystem of tissues, including linear, branching, focuses on novel approaches to mitigate these challenges using neutral, and punctuated patterns. Recent evidence in breast bulk tumor, liquid biopsies, single-cell analysis, and deep cancer favors branching and punctuated evolution driven by sequencing techniques. The origins of intratumor heterogene- genome instability as well as nongenetic sources of heteroge- ity and the clinical, diagnostic, and therapeutic consequences neity, such as epigenetic variation, hierarchal tumor cell orga- in breast cancer are also explored. Mol Cancer Res; 15(9); 1127–37. nization, and subclonal cell–cell interactions.
    [Show full text]
  • Intra-Tumor Heterogeneity from a Cancer Stem Cell Perspective Pramudita R
    Prasetyanti and Medema Molecular Cancer (2017) 16:41 DOI 10.1186/s12943-017-0600-4 REVIEW Open Access Intra-tumor heterogeneity from a cancer stem cell perspective Pramudita R. Prasetyanti1,2 and Jan Paul Medema1,2,3* Abstract Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). The latter includes phenotypic diversity such as cell surface markers, (epi)genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure. Cancer stem cells (CSCs) have been put forward to be one of the determining factors that contribute to intra-tumor heterogeneity. However, recent findings have shown that the stem-like state in a given tumor cell is a plastic quality. A corollary to this view is that stemness traits can be acquired via (epi)genetic modification and/or interaction with the tumor microenvironment (TME). Here we discuss factors contributing to this CSC heterogeneity and the potential implications for cancer therapy. Keywords: Tumor heterogeneity, Cancer stem cell, Stemness, Tumor microenvironment Background tumor and microenvironment heterogeneity determine A tumor is a heterogeneous population of cells, containing the fitness of the tumor and as such, are likely to be transformed cancer cells, supportive cells and tumor- crucial factors in treatment success. infiltrating cells. This intra-tumor heterogeneity is further Two models have been proposed to account for hetero- enhanced by clonal variation and microenvironmental geneity within a tumor. In the clonal evolution model, influences on cancer cells, which also do not represent a stochastic mutations in individual tumor cells serve as homogeneous set of cells.
    [Show full text]
  • A Population Genetics Perspective on the Determinants of Intra-Tumor Heterogeneity☆
    BBACAN-88143; No. of pages: 18; 4C: 2, 6, 8, 9, 10 Biochimica et Biophysica Acta xxx (2017) xxx–xxx Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan A population genetics perspective on the determinants of intra-tumor heterogeneity☆ Zheng Hu, Ruping Sun, Christina Curtis ⁎ Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA article info abstract Article history: Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs Received 16 December 2016 over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at differ- Received in revised form 1 March 2017 ent stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of can- Accepted 2 March 2017 cer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic Available online xxxx variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implica- tions for precision medicine, the accurate quantification of heterogeneity within and between tumors has be- come a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evi- dence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity.
    [Show full text]
  • Heterogeneity in Breast Cancer and the Problem of Relevance of findings
    53 Mini review Heterogeneity in breast cancer and the problem of relevance of findings ∗ M. Aubele a, and M. Werner b these events has not been established. Furthermore, the a GSF – National Research Center for Environment relationship between histological progression and ge- and Health, Institute of Pathology, Neuherberg, netic events in breast cancer is not yet well defined. Germany This review discusses the cytogenetic and molecular b Technische Universität München, Klinikum rechts genetic findings published within the last years, the der Isar, Institute of Pathology, Munich, Germany problem of correlating molecular-biological data with histology, and, consequently, the difficulties in devel- Received 15 August 1999 oping a model for breast cancer progression. Accepted 16 November 1999 Many attempts are made to identify critical genetic events re- 2. Evidences for intratumoural heterogeneity sponsible for the development and progression of breast can- cer. There is increasing evidence that breast cancer is a het- Intratumour phenotypic heterogeneity is one of the erogeneous disease, both, phenotypically as well as with re- characteristics of breast carcinoma, and genetic mech- spect to its molecular biologically. It is, therefore, extremely anisms are likely to contribute to it [39]. Heteroge- difficult to establish a diagnostically and prognostically rel- neous molecular findings in different parts of a tumour evant tumourigenesis model. Emerging new techniques such may reflect concomitant or successive clonal develop- as microarrays, will provide us with a wealth of additional ment. No studies have yet been carried out to make a data over the next years. The precise sampling of tumour ma- comprehensive analysis of known genetic alterations.
    [Show full text]
  • The Role of Tumour Heterogeneity and Clonal Cooperativity in Metastasis, Immune Evasion and Clinical Outcome Deborah R
    Caswell and Swanton BMC Medicine (2017) 15:133 DOI 10.1186/s12916-017-0900-y REVIEW Open Access The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome Deborah R. Caswell1* and Charles Swanton1,2 Abstract Background: The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. Discussion: Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability. Conclusions: We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens.
    [Show full text]
  • Tumor Heterogeneity: a Central Foe in the War on Cancer Jane De Lartigue, Phd
    Feature New Therapies Tumor heterogeneity: a central foe in the war on cancer Jane de Lartigue, PhD major challenge to effective cancer treat- develop – the clonal evolution model and the cancer ment is the astounding level of heteroge- stem cell (CSC) model (Figure 1). neity that tumors display on many different Afronts. Here, we discuss how a deeper appreciation of The clonal evolution model this heterogeneity and its impact is driving research As cells divide, they randomly acquire mutations as a efforts to better understand and tackle it and a radi- result of DNA damage. The clonal evolution model cal rethink of treatment paradigms. posits that cancer develops as the result of a multi- step accumulation of a series of “driver” mutations A complex and dynamic disease that confer a promalignant advantage to the cell and The nonuniformity of cancer has long been appre- ultimately fuel a cancerous hallmark. ciated, reflected most visibly in the variation of This evolution can occur in a linear fashion, response to the same treatment across patients with whereby the emergence of a new driver mutation the same type of tumor (inter-tumor heterogene- conveys such a potent evolutionary advantage that it ity). The extent of tumor heterogeneity is being fully outcompetes all previous clones. There is limited evi- realized only now, with the advent of next-genera- dence for linear evolution in most advanced human tion sequencing technologies. Even within the same cancers; instead, they are thought to evolve predom- tumor, there can be significant heterogeneity from inantly through a process of branching evolution, in cell to cell (intra-tumor heterogeneity), yielding which multiple clones can diverge in parallel from a substantial complexity in cancer.
    [Show full text]
  • Cancer Stem Cells in Glioblastoma
    Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Cancer stem cells in glioblastoma Justin D. Lathia,1,2 Stephen C. Mack,3 Erin E. Mulkearns-Hubert,1 Claudia L.L. Valentim,3 and Jeremy N. Rich2,3 1Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; 2Department of Molecular Medicine, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA; 3Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Tissues with defined cellular hierarchies in development tumors will develop resistance to overcome initially effec- and homeostasis give rise to tumors with cellular hierar- tive therapies that poison driving oncogenes. chies, suggesting that tumors recapitulate specific tissues Glioblastoma (GBM; World Health Organization grade and mimic their origins. Glioblastoma (GBM) is the IV glioma) is the most prevalent and lethal primary in- most prevalent and malignant primary brain tumor and trinsic brain tumor (Stupp et al. 2009). Unlike other solid contains self-renewing, tumorigenic cancer stem cells tumor cell types, GBM widely invades the surrounding (CSCs) that contribute to tumor initiation and thera- brain but rarely metastasizes to other organs. While halt- peutic resistance. As normal stem and progenitor cells ing steps to fight GBM are being made using targeted participate in tissue development and repair, these de- therapies (e.g., bevacizumab) or immunotherapies, GBM velopmental programs re-emerge in CSCs to support the therapy remains focused on achieving maximal surgi- development and progressive growth of tumors.
    [Show full text]
  • Future Medical Applications of Single-Cell Sequencing in Cancer Nicholas Navin*1,2 and James Hicks3
    Navin and Hicks Genome Medicine 2011, 3:31 http://genomemedicine.com/content/3/5/31 REVIEW Future medical applications of single-cell sequencing in cancer Nicholas Navin*1,2 and James Hicks3 Abstract thus complicate the inter- and intra-tumor comparisons, which are the basis of molecular classification methods. Advances in whole genome amplication and next- In addition, solid tumors are often composed of generation sequencing methods have enabled genomic multiple clonal subpopulations [1-3], and this analyses of single cells, and these techniques are now heterogeneity further confounds the analysis of clinical beginning to be used to detect genomic lesions in samples. Single-cell genomic methods have the capacity individual cancer cells. Previous approaches have been to resolve complex mixtures of cells in tumors. When unable to resolve genomic dierences in complex multiple clones are present in a tumor, molecular assays mixtures of cells, such as heterogeneous tumors, despite reflect an average signal of the population, or, the importance of characterizing such tumors for alternatively, only the signal from the dominant clone, cancer treatment. Sequencing of single cells is likely to which may not be the most malignant clone present in improve several aspects of medicine, including the early the tumor. is becomes particularly important as detection of rare tumor cells, monitoring of circulating molecular assays are employed for directing targeted tumor cells (CTCs), measuring intratumor heterogeneity, therapy, as in the use of ERBB2 (Her2-neu) gene and guiding chemotherapy. In this review we discuss amplification to identify patients likely to respond to the challenges and technical aspects of single-cell Herceptin (trastuzumab) treatment in breast cancer, sequencing, with a strong focus on genomic copy where 5% to 30% of all patients have been reported to number, and discuss how this information can be used exhibit such genetic heterogeneity [4-7].
    [Show full text]
  • A Deep Convolutional Neural Network for Segmentation of Whole-Slide
    www.nature.com/bjc ARTICLE AI Applied to Cancer A deep convolutional neural network for segmentation of whole-slide pathology images identifies novel tumour cell- perivascular niche interactions that are associated with poor survival in glioblastoma Amin Zadeh Shirazi 1,2, Mark D. McDonnell 2, Eric Fornaciari3, Narjes Sadat Bagherian4, Kaitlin G. Scheer 1, Michael S. Samuel 1,5, Mahdi Yaghoobi6, Rebecca J. Ormsby 7, Santosh Poonnoose 7,8, Damon J. Tumes 1 and Guillermo A. Gomez 1 BACKGROUND: Glioblastoma is the most aggressive type of brain cancer with high-levels of intra- and inter-tumour heterogeneity that contribute to its rapid growth and invasion within the brain. However, a spatial characterisation of gene signatures and the cell types expressing these in different tumour locations is still lacking. METHODS: We have used a deep convolutional neural network (DCNN) as a semantic segmentation model to segment seven different tumour regions including leading edge (LE), infiltrating tumour (IT), cellular tumour (CT), cellular tumour microvascular proliferation (CTmvp), cellular tumour pseudopalisading region around necrosis (CTpan), cellular tumour perinecrotic zones (CTpnz) and cellular tumour necrosis (CTne) in digitised glioblastoma histopathological slides from The Cancer Genome Atlas (TCGA). Correlation analysis between segmentation results from tumour images together with matched RNA expression data was performed to identify genetic signatures that are specific to different tumour regions. RESULTS: We found that spatially resolved gene signatures were strongly correlated with survival in patients with defined genetic mutations. Further in silico cell ontology analysis along with single-cell RNA sequencing data from resected glioblastoma tissue samples showed that these tumour regions had different gene signatures, whose expression was driven by different cell types in the regional tumour microenvironment.
    [Show full text]
  • Heterogeneity in Cancer Stem Cells
    Cancer Letters 357 (2015) 63–68 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Mini-review Heterogeneity in cancer stem cells Anxin Wang a,b,c,1, Lisha Chen a,b,c,1, Chunlin Li a,b,c, Yimin Zhu a,* a Key Laboratory for Nano-Bio Interface Research, Suzhou Key Laboratory for Nanotheranostics, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China b Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China c University of Chinese Academy of Sciences, Beijing 100049, China ARTICLE INFO ABSTRACT Article history: Accumulating evidence suggests that cancer stem cells (CSCs) are heterogeneous populations and their Received 30 September 2014 phenotypes are unstable. A number of intrinsic and extrinsic mechanisms contribute to CSC phenotypic Received in revised form 18 November variation. The existence of various CSC subpopulations which would lead to a rapid relapse after primary 2014 treatments might pose a problem for CSC targeted therapeutics. In order to develop more effective ap- Accepted 18 November 2014 proaches to cancer therapeutics, more CSC-related surface markers or targeting molecules, as well as some novel targeting strategies should be explored. This review summarized the origin and performance of Keywords: heterogeneity in CSCs and discussed their therapeutic implications. Cancer stem cell Heterogeneity © 2014 Elsevier Ireland Ltd. All rights reserved. Surface marker Targeting therapy Introduction which cause heterogeneous in macroscopic feature, microscope ap- pearance and clinical outcomes, define the heterogeneity of CSCs In the past two decades, significant progress has been made in [20].
    [Show full text]
  • Tumor Heterogeneity: a Great Barrier in the Age of Cancer Immunotherapy
    cancers Review Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy Nader El-Sayes 1,†, Alyssa Vito 1,† and Karen Mossman 2,* 1 Department of Biochemistry and Biomedical Sciences, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; [email protected] (N.E.-S.); [email protected] (A.V.) 2 Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada * Correspondence: [email protected] † These authors contributed equally to this publication. Simple Summary: Despite great advances in cancer therapy, tumor heterogeneity continues to be a great barrier for the successful treatment of cancer. It has long been established that tumor heterogeneity is prevelant in most cancer patients and is a major driver of acquired resistance to all forms of cancer therapy. In the case of immunotherapy, the response of the immune system against specific tumor antigens can drive selective pressure towards antigen-negative cells, which is a common cause of relapse in the clinic. In this review we summarize the mechanisms in which tumor heterogeity can arise. Furthermore, we discuss recent advances in the field of oncology that can be used to better identify, study, and overcome tumor heterogeneity. Abstract: Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase Citation: El-Sayes, N.; Vito, A.; selective pressure towards subpopulations with acquired resistance.
    [Show full text]
  • UNDERSTANDING CANCER: Tumour Heterogeneity
    PIP Digest UNDERSTANDING CANCER: Tumour Heterogeneity The genetic diversity or ‘heterogeneity’ of cancer makes it a complex and challenging disease. This PIP Digest explains what the concept of tumour heterogeneity means for cancer treatment. Key Concepts • Intratumour heterogeneity • Clonal evolution • Cancer stem cells Related PIP Digests • Understanding Cancer: Epigenetics 101 • Understanding Cancer: Cancer Biomarker Basics • Clinical Trials: Precision Medicine and Clinical Trials “Every individual specimen of cancer is its own individual specimen of cancer. We have not encountered in our history a disease where every single instance of the disease is its own instance of the disease. That is a unique thing about cancer." -- Siddhartha Mukherjee (2017) For a very long time, cancer was considered a mass of fast-growing cells with similar mutations that could respond if only researchers could fine an effective treatment. Over time, though, researchers discovered that cancer not only varies between patients (interpatient heterogeneity), but that there is variation within one person’s tumours (intertumour heterogeneity) and even within a single tumour (intratumour heterogeneity). Tumour heterogeneity describes differences in cancer cells’ shape and structure (morphology), gene expression, metabolism, and capacity to move, proliferate, and metastasize. For example, prostate cancer has been described as “multi-focal.” This means that men with prostate cancer often have multiple tumours, each of which evolves independently and has different mutations. These variations greatly affect clinical care. A single biopsy or tissue sample cannot reveal the variability among and within tumours. A treatment plan made on partial information will likely fail to eradicate the cancer. 1 PIP Digest Tumour Heterogeneity From: https://www.ous-research.no/lothe/?k=lothe%2Fcancer+type&aid=14844 The heterogeneity of tumours is the key reason why effective cancer treatment is so challenging.
    [Show full text]