Metastasis is often accompanied by radio- and chemotherapeutic resistance to anticancer treatments and is the major cause of death in cancer patients. Better understanding of how cancer cells circumvent therapeutic insults and how disseminated cancer clones generate life-threatening metastases would therefore be paramount to the development of effective therapeutic approaches for clinical management of malignant disease. Mounting reports over the past two decades have provided evidence for the existence of a minor population of highly malignant cells within liquid and solid tumors, which are capable of self-renewing and of regenerating secondary growths with the heterogeneity of the primary tumors from which they derive. These cells, called tumor-initiating cells or cancer stem cells (CSCs) exhibit increased resistance to standard radio- and chemotherapies and appear to have mechanisms that enable them to evade immune surveillance. CSCs are therefore considered to be responsible for systemic residual disease after cancer therapy, as well as for disease relapse. How CSCs develop, the nature of the interactions they establish with their microenvironment, their phenotypic and functional characteristics, as well as their molecular dependencies have all taken center stage in cancer therapy. Indeed, improved understanding of CSC biology is critical to the development of important CSC-based anti-neoplastic approaches that have the potential to radically improve cancer management. Here, we summarize some of the most pertinent elements regarding CSC development and properties, and highlight some of the clinical modalities in current development as anti-CSC therapeutics.
Cancer biomarker, cancer stem cell, tumor-initiating cell, microenvironment, signaling pathway, targeted therapy, radioresistance, chemoresistance
Antoine E Karnoub has nothing to declare in relation to this article. Catherine L Amey is an employee of Touch Medical Media, Goring-On-Thames, UK.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
February 22, 2017 Accepted
April 20, 2017
Antoine E Karnoub, Center for Life Science 0634, 3 Blackfan Circle, Boston, MA 02215, US. E: firstname.lastname@example.org
The publication of this article was supported by Boston Biomedical, who was given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Despite substantial advances in cancer diagnosis and treatment, the long-term survival rate for many cancer patients remains dismal.1 More than 90% of cancer-related mortality is ascribed to disease resurgence months or years after adjuvant therapy, either in the form of local recurrence or in the form of metastatic spread, which are typically refractory to existing treatment modalities (see Table 1).1,2 Novel anti-neoplastic therapeutic approaches aimed at eradicating residual relapsing disease are therefore sorely needed, but remain to be defined.
The cornerstone of current cancer management approaches relies on early detection and on chemotherapeutic and radiologic treatment of diagnosed neoplasms. Although detection methodologies have helped significantly in reducing the lethality associated with cancers such as prostate or breast neoplasms, they have had limited widespread efficacy in many others. Indeed, efforts to diagnose cancers early in their development are still hampered by serious limitations in technologies that cannot detect small tumorigenic growths or disseminated microscopic disease. Similarly, classical anti-neoplastic treatments, which target highly proliferating cancer cells, nondiscriminately target bystander normal cells, such as hair follicle cells or gut-regenerating cells, causing high degree of systemic toxicity. In addition, these systemic therapies, are, to a large extent, inefficient in eradicating disseminated disease, and often result in the emergence of resistance.
The discovery that unchallenged human primary tumors harbor subpopulations of cancer cells that are distinguished from bulk populations by exclusive abilities to self-renew and generate heterogeneous secondary growths refocused attention on understanding the fundamental biology of how these cells emerge, and on identifying means to kill them. Such tumor-initiating cells (TICs), dubbed cancer stem cells (CSCs), which pre-exist already in untreated tumors, were found to be amplified in recurrent disease, and were shown to be highly malignant and with augmented tolerance to existing radio- and chemotherapeutics.3 Indeed, it is widely accepted that CSCs represent the root cause for metastatic dissemination and disease relapse in cancer patients. As such, the identification of effective CSC-specific therapeutics has taken center stage in the development of anti-neoplastic therapies aimed at eradicating disease relapse.4
The molecular underpinnings of the CSC state have been extensively reviewed over the past several years, for example, by Bandhavkar,5 Kuhlman et al.,6 and others.7–17 The purpose of this article is to briefly summarize and highlight some of the most pertinent concepts surrounding CSC biology, as well as current and emerging therapies targeting CSCs. Bulleted format has been used to provide a more concise presentation of these broad topics to clinicians and researchers interested in an introduction to CSC research.
Revival of the cancer stem cell hypothesis
• In the 1860s, Rudolf Virchow observed microscopic similarities between cancer (in this case, teratocarcinoma) and developing embryonic tissues; this led him to postulate that cancers derive from embryonic-like cells.18
• The concept that cancers originate from cells with stem cell characteristics was re-formulated by Julius Cohnheim.19,20 His theory, termed “embryonal rest hypothesis”, stated that cancers initiate from tissue-resident stem cells left over from embryogenesis, which remain dormant in such tissues until reawakened later in life to give rise to cancer.
• Cancer’s potential origin from embryonic/germinal-like progenitor cells that are inadvertently stimulated to grow uncontrollably in adult tissues was again entertained by Durante,21 Beard,22 Rippert,23 and Rotter.24
• The idea that tumors contain cancer populations with special malignant properties was re-visited by many researchers, such as Hewitt in 1953, who noted that variations in tumor-initiating potential and transplantability exist among varying inocula of sarcoma suspensions,25 or by McCulloch et al. in 1971,26 who found that tumor colony-forming cells possessed different growth characteristics than their normal counterparts, and that the so-called tumor stem cells represented a very small percentage (0.01–1%) of the whole tumor population.
• In landmark studies published in 1989, 1994, and 1997,27–29 John Dick’s group used a model of acute myeloid leukemia (AML) to definitively show that AML was hierarchical in nature, that cells capable of serially initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease were rare, and that they possessed selfrenewal, proliferative, and differentiation capacities consistent with “true” leukemia stem cells.
• Chia-Cheng Chang and colleagues isolated two types (type I and II) of antigenically and phenotypically different normal epithelial cells from human breast tissue, and showed that only one type (type I, with luminal characteristics) is prone for transformation by SV40.30 Interestingly, type I could be stimulated to generate type II cells (with basal characteristics), prompting the hypothesis that cancers may originate from specialized progenitor-like cells pre-existing in solid tissues.
• Using a model in which human breast cancer cells were grown in immunocompromised mice, Al-Hajj and colleagues demonstrated that not all cancer cells within carcinomas are equally tumorigenic and that only a small subset of cells within such tumors is able to generate secondary tumors when transplanted.31
These observations suggested that solid cancers are, like liquid cancers,28 also hierarchical in nature, and harbor a small proportion of so-called tumor-initiating CSCs (also termed TICs).
• Cancer cells from several species were shown to exhibit stark activation patterns in molecular networks that otherwise function as critical regulators of embryonic, adult, and induced pluripotent stem cell homeostasis.32–35
• TICs/CSCs have now been identified in multiple malignancies, including multiple leukemias and various solid tumors36 such as lung,37 colon,38 prostate,39 ovarian,40 brain,41 and skin cancers.42
• Tumor transplantation studies in histocompatible mice suggested that CSCs can be more abundant than previously estimated, constituting as much as 10% in leukemias and lymphomas,43 and as much as 25% in melanomas.44
• The proportions of CSCs within tumors correlate positively with poor prognosis.45
Characteristics of cancer stem cells
• Normal self-renewing adult tissue stem cells give rise to progenitor cells that are often termed transit-amplifying cells which, in turn, divide and proliferate to engender more differentiated cells with restricted proliferating and clonogenic potentials. This hierarchical system calls upon stem cells (which sit at the top of the pyramid) to expand when more differentiated cells (laying at the bottom of the tissue pyramid) are depleted.
• The self-renewing ability of these stem cells ensures their continued presence within tissues and the balance between stem and differentiated cells ascertains tissue homeostasis.
• Normal stem cells are in constant interactions with their microenvironment, or niche, which tightly regulates stem cell state maintenance while controlling the expansion of the stem cell compartment.
• Tumors are formed of heterogeneous cancer cells that are organized in a hierarchy similar to that of normal tissues, and contain CSCs that share several characteristics with normal stem cells.
• The 2006 American Association for Cancer Research Workshop on Cancer Stem Cells defined a CSC as “a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor.”46
• In this model, each tumor contains a sub-population of cells (the CSCs) that are able to divide asymmetrically in order to self-renew and give rise to a phenotypically distinct daughter cell. CSCs are thus considered to be the source of all aggressive plastic cancer cells present in a malignant tumor.2
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Cancer biomarker, cancer stem cell, tumor-initiating cell, microenvironment, signaling pathway, targeted therapy, radioresistance, chemoresistance