The Increasing Complexity of the Cancer Stem Cell Paradigm

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Science (Impact Factor: 33.61). 07/2009; 324(5935):1670-3. DOI: 10.1126/science.1171837
Source: PubMed


The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain
topics of considerable controversy. Opinions about the validity of the CSC hypothesis, the biological properties of CSCs,
and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate,
the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated
by considering cancer as a problem in stem cell biology.

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Available from: Craig T. Jordan, Dec 30, 2014
    • "These CSCs or TPCs need not be rare but would either initiate or maintain tumor growth and must therefore be specifically targeted to prevent malignant progression and recurrence. Although this work originated in leukemia [22], a large number of studies have since been published on TPCs in solid tumors [20,21,23]. For example, Singh et al. demonstrated that isolation of a rare cell subpopulation based on CD133 cell surface expression selected for a brain tumor stem cell phenotype both in vitro and in vivo [24,25]. "
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    ABSTRACT: Brain tumors such as medulloblastoma exhibit various genomic alterations, gene expression profiles, and responses to treatment. This extensive heterogeneity has revealed a critical need for variant-specific, functionally validated biomarkers and therapeutic strategies. Whereas CD133 was the first cell surface marker utilized to isolate putative brain tumor-propagating cells, studies have shown that these cells are not exclusive to the CD133+ fraction. Attempts to identify new cell surface markers have uncovered a novel role for CD271/p75NTR in isolating self-renewing medulloblastoma cells. To identify additional markers, studies are now utilizing high-throughput flow cytometry cell surface marker screening platforms for novel comparative analysis of cell phenotypes. Using this strategy, one can determine whether candidate biomarkers can be employed not only for isolation of specific tumor cell phenotypes but also for stratification of tumors into a particular subgroup.
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    • "Therefore, CSCs stand at the apex of a tumor cell hierarchy. They resemble functional similarities to normal somatic stem cells, that is, hematopoietic stem cells (HSCs) with their capacity to renew themselves and to give rise to all mature blood cell lineages [14] [15]. A common terminology for cells with specific properties in ALL used in this review should be introduced: the leukemic cell of origin (LCO) is the first cell carrying the initial preleukemic lesion. "
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    ABSTRACT: Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients' outcome in ALL.
    Full-text · Article · Aug 2015 · Stem cell International
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    • "relatively small number of investigators initially focused on understanding the roles of 131 stem cells in mammary gland development, numerous investigators have now entered the 132 field, leading to an explosion of studies aimed at understanding the cell of origin of 133 different breast cancer subtypes as well as the mechanisms responsible for therapeutic 134 resistance and metastasis. Thus, the application of the stem cell paradigm to solid cancers 135 and its potential importance in both etiology and treatment has led to a better appreciation 136 of the potential mechanisms responsible for both inter-and intratumoral heterogeneity in 137 breast cancer (Rosen & Jordan 2009). In the following review, we will discuss several of 138 these concepts in detail by focusing primarily on the extensive work performed in mouse 139 models of mammary gland development and tumorigenesis, while directing the reader to 140 comprehensive reviews on studies concerning stem cells in the human breast (Petersen & 141 Polyak 2010; Visvader & Stingl 2014). "
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    ABSTRACT: The mammary gland is a dynamic organ that undergoes extensive morphogenesis during the different stages of embryonic development, puberty, estrus, pregnancy, lactation and involution. Systemic and local cues underlie this constant tissue remodeling and act by eliciting an intricate pattern of responses in the mammary epithelial and stromal cells. Decades of studies utilizing methods such as transplantation and lineage tracing have identified a complex hierarchy of mammary stem cells, progenitors and differentiated epithelial cells that fuel mammary epithelial development. Importantly, these studies have extended our understanding of the molecular crosstalk between cell types, and signaling pathways maintaining normal homeostasis that often are deregulated during tumorigenesis. While several questions remain, this research has many implications for breast cancer. Fundamental among these are the identification of the cells of origin for the multiple subtypes of breast cancer and the understanding of tumor heterogeneity. A deeper understanding of these critical questions will unveil novel breast cancer drug targets and treatment paradigms. In this review, we provide a current overview of normal mammary development and tumorigenesis from a stem cell perspective.
    Preview · Article · Jul 2015 · Endocrine Related Cancer
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