DOCSLIB.ORG

Cancer Stem Cells in Glioblastoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. Elucida- cal resection followed by concurrent radiation therapy tion of the molecular mechanisms that govern CSCs has with temozolomide (TMZ; an orally available methyla- informed the development of novel targeted therapeutics tion chemotherapy) and subsequent additional adjuvant for GBM and other brain cancers. CSCs are not self-auton- TMZ therapy. Conventional treatment offers patients omous units; rather, they function within an ecological with GBM additional survival time with generally accept- system, both actively remodeling the microenvironment able quality of life, but a cure is never achieved. GBM and receiving critical maintenance cues from their niches. represents one of the most comprehensively genomi- To fulfill the future goal of developing novel therapies to cally characterized cancer types, leading to recognition collapse CSC dynamics, drawing parallels to other normal of groups of tumors defined by transcription profiles (pro- and pathological states that are highly interactive with neural, neural, classical, and mesenchymal), genetics their microenvironments and that use developmental sig- (mutations of isocitrate dehydrogenase 1 [IDH1]), and epi- naling pathways will be beneficial. genetics (CpG island methylator phenotype [CIMP]) (Weller et al. 2013). Long-term survivors are often, but not exclusively, patients with tumors harboring muta- tions in IDH1, which likely represent a different disease Development is a coordinated summation of the individ- than most GBMs. Beyond IDH1 mutations and a few ual cellular dynamics that build an organ, and the pro- other biomarkers (deletion of chromosomes 1p and 19q grams responsible for this construction are generally in oligodendrogliomas, methyl guanine methyltransfer- preserved in stem cells for organ homeostasis and tissue ase [MGMT] promoter methylation, etc.), the accumulat- repair. Tumors are complex systems that recapitulate the ed genetic characterization of GBMs has failed to impact complexity of organs or tissues with dynamic regulation clinical practice, suggesting that other discovery para- and constituent cellular populations during tumor initia- digms should also be considered. tion, maintenance, and progression (Hanahan and Wein- The brain, like other organs with clearly defined cellu- berg 2011). While many scientists have sought to reduce lar hierarchies in development and homeostasis (e.g., — the complexity of cancer to a one-dimensional process blood, breast, skin, and colon), gives rise to tumors with for example, characterizing cancers solely based on genet- defined cellular hierarchies, suggesting that cancer repli- — ics most advanced cancers unfortunately remain nearly cates ontogeny (Reya et al. 2001). Atop the apex of cellular as lethal since the declaration of the War on Cancer in hierarchies are stem cells, which have been assumed to 1971. Targeted therapeutics offer a transient benefit for be rare, quiescent, self-renewing cells, but several highly some cancer types with driving mutations, but even these © 2015 Lathia et al. This article is distributed exclusively by Cold Spring [Keywords: brain tumor; cancer stem cell; glioblastoma; glioma; stem Harbor Laboratory Press for the first six months after the full-issue cell; tumor-initiating cell] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.261982. (Attribution-NonCommercial 4.0 International), as described at http:// 115. creativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 29:1203–1217 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/15; www.genesdev.org 1203 Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Lathia et al. proliferative organs (e.g., the intestine and skin) contain hierarchies, from their differentiated progeny remains at least two pools of stem cells: one quiescent, and the challenging; however, stem cell biology faces a similar dif- other highly proliferative (Barker et al. 2010). Stem cells ficulty with normal stem cell identification. Of note, the generate transient amplifying cells, which in turn create CSC hypothesis does not claim a stem cell as the cell of or- lineage-restricted progeny that are eventually fated to be- igin for cancers, suggesting that CSCs do not need to ad- come the terminally differentiated effector cells. here to all of the observed features of normal stem cells. Neural stem and progenitor cell (NSPC) pools vary in lo- In the following sections, we provide an update on in- cation and control during development, suggesting that trinsic and extrinsic regulators of the CSC state in GBM different cellular hierarchies may be co-opted by brain tu- and discuss how the integration of genetics, epigenetics, mors (Gibson et al. 2010; Lottaz et al. 2010). Informed and metabolism has shaped our understanding of how by techniques used to enrich and characterize NSPCs, CSCs function to drive GBM growth. We also highlight fu- several groups in parallel demonstrated that gliomas and ture opportunities to further understand the complexity other primary brain tumors contain self-renewing, tumor- of CSC regulation through interaction with other cells (in- igenic cells (Ignatova et al. 2002; Hemmati et al. 2003; cluding immune cells) and how the translation of CSC- Singh et al. 2003, 2004; Galli et al. 2004). The nomencla- based therapies needs to take into account the cellular dy- ture for these cells has been controversial (as discussed be- namics of CSCs, which rely on developmental signaling low), with the dominant choice being cancer stem cells programs. (CSCs) or tumor-initiating cells (importantly, these terms are not identical, as a CSC designation is more restrictive The history of the CSCs but also more informative) (Table 1). Unlike normal brain organization—where the generation of differentiated prog- The heterogeneity of tumor cells has long been appreci- eny is stage-specific (neurons and then glia during devel- ated, but two decades ago, seminal work from Dick’s labo- opment) and derived from rapidly dividing progenitor ratory (Bonnet and Dick 1997) described the isolation of a cells and quiescent, multipotent stem cells that persist leukemia-initiating cell, the first purification of cancer into adulthood and become activated upon differentiation stem-like cells, a population of cells that had originally (Rowitch and Kriegstein 2010)—these populations have been proposed to exist >150 years earlier (Sell 2004). The yet to be delineated in brain tumors. The ability to distin- first prospective isolation of human NSPCs was performed guish between self-renewing cells with stem and progeni- using CD133 (Uchida et al. 2000) and prompted a search tor cell cycle properties and transcriptional signatures is for brain tumor cells that shared the characteristics of likely to provide clarity with respect to nomenclature NSPCs. A burst of studies soon followed describing brain and the functional interplay between cells at the apex of CSCs in anaplastic astrocytoma (Ignatova et al. 2002), me- the hierarchy. The challenges distinguishing CSCs from dulloblastoma, pilocytic astrocytoma, ependymoma, gan- their progeny are derived, in part, from the limited recogni- glioglioma (Hemmati et al. 2003; Singh et al. 2003), and tion of points of relative stability (“attractor states”) in the GBM (Ignatova et al. 2002; Hemmati et al. 2003; Galli landscape of cellular identity that define the stem cell state et al. 2004). Brain CSCs have subsequently been shown and transitions into (dedifferentiation) and out of (differen- to be
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]
  • 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]
  • 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].
    [Show full text]