Cellular heterogeneity represents one of the greatest challenges in cancer therapeutics. Basal cells were previously identified as a cell of origin for pca, but increasing evidence implicates luminal cells as a preferred cell of origin for pca, as well as key drivers of tumor development and progression. Hjelmeland1 abstract our understanding of intratumoral heterogeneity in cancer continues to evolve, with. Intratumor heterogeneity from a cancer stem cell perspective. Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Commentary open access understanding breast cancer. Heterogeneity within and between tumors is a wellknown phenomenon that greatly complicates the diagnosis and treatment of cancer. Phenotypic and functional heterogeneity is one of the hallmarks of human cancers.
The plastic cancer stem cell theory describes a third and evolving model in which. Pdf understanding the cancer stem cell researchgate. Cscs have been shown in numerous cancer models to be involved in tumor development, cell proliferation, and metastatic dissemination, while. These are the cancer stem cell model and the clonal evolution model. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. Intratumor heterogeneity from a cancer stem cell perspective pramudita r. The latter includes phenotypic diversity such as cell surface markers, epigenetic abnormality, growth rate, apoptosis and other hallmarks of cancer that. Heterogeneity is evident between cancers from different patients intertumor heterogeneity and within a single tumor intratumor heterogeneity. Accordingly, cscs reside at the apex of the hierarchy and are thought to possess the majority of a cancers tumorinitiating and metastatic ability. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. Understanding the cancer stem cell pubmed central pmc. Metabolomic mapping of cancer stem cells for reducing and.
Functional and phenotypic heterogeneity occur in a tumors cancer cells due to environmental differences, genetic chance and various reversible changes taking place in the cancer cell population. Epithelialmesenchymal plasticity is the bestknown case of tumor cell plasticity, but recent work has uncovered other examples, often with functional consequences. The deeper silencing of stemcellrelated genes with this abnormal dna methylation andor transcriptionally repressive chromatin could reduce the plasticity of cell population changes and help lock in cell clones with abnormal retention of selfrenewal capacity at the expense of capacity for differentiation easwaran et al. The majority of tumors display substantial degree of phenotypic and functional heterogeneity at the population level. To demonstrate the functionality of the candidate stem cells, markerpurified or enriched cells are used in syngeneic, allogeneic, or xeno transplantation assays to assess whether such cells can reconstitute or regenerate the tissues from which the cells are. Accordingly, cscs reside at the apex of the hierarchy and are thought to possess the majority of a cancer s tumorinitiating and metastatic ability. Many names have been used to identify this population but the term cancer stem cell. The alternative cancer stem cell csc model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Towards understanding cancer stem cell heterogeneity in. These are a dangerous duo that can cooperatively promote tumor progression, metastasis, therapy resistance, and tumor relapse 6. They examined cancer stem cell plasticity in which cancer stem cells can transition between noncancer stem cells noncsc and csc via in situ supporting a more stochastic model. Recent cancer genome projects unexpectedly highlighted the role of epigenetic alterations in cancer development. The presence of heterogeneous subsets of cancer stem cells cscs remains a.
Prostate luminal progenitor cells in development and cancer. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are. Heterogeneity within a given cancer arises from diverse cell types recruited to the. Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. However, in the past, owing to a lack of discerning investigative tools, we had. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells remarkable ability to undergo epithelialnoncancer stem cell csc to mesenchymalcsc emcsc plasticity. Most stem cells in adult tissuesorgans are identified by cell surface markers. Therapeutic implications of cellular heterogeneity and. Jan 02, 2019 the presence of heterogeneous subsets of cancer stem cells cscs remains a clinical challenge. It is not known which clinical behaviors are explained by the. Epithelialtomesenchymal plasticity of cancer stem cells. The presence of heterogeneous subsets of cancer stem cells cscs remains a clinical challenge. Libby1, jonathan mcconathy2, victor darleyusmar3, and anita b. These subsets often occupy different regions in the primary tumor and have varied epithelialmesenchymal phenotypes.
Epigenetic heterogeneity in cancer biomarker research. Jan 01, 20 the alternative cancer stem cell csc model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Jul 23, 20 human breast cancer bc is one of the leading causes of death for women worldwide, and is characterized by a group of highly heterogeneous lesions. The emerging concept of cell plasticity and reciprocity to change the phenotype by processing signals from the environment throws more light on the actual complexity of tumor heterogeneity than can be expected solely from a unidirectional, classical cancer stem cell csc model.
The major limitations in bc research include the high flexibility rate of breast cancer stem cells bcscs and the difficulty of. According to this model, the identification of targeted therapies to remove the cscs would lead to tumor regression. Tumor heterogeneity and cancer stem cell paradigm wiley online. The role of metabolic plasticity in blood and brain stem cell. Understanding cancer stem cell heterogeneity and plasticty. It is not known which clinical behaviors are explained by the stem cell model and which cancers follow this model. Toward understanding cancer stem cell heterogeneity in the tumor. Jul 10, 2019 cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drugrefractory cell populations, ultimately leading to therapy failure. He is particularly interested in the plasticity of cancer stem cell subpopulations, the molecular mechanisms driving plasticity, and how plastic subpopulations can be modelled in vitro to uncover their role in cancer. The deeper silencing of stem cell related genes with this abnormal dna methylation and or transcriptionally repressive chromatin could reduce the plasticity of cell population changes and help lock in cell clones with abnormal retention of selfrenewal capacity at the expense of capacity for differentiation easwaran et al.
The process of cancer stem cell plasticity in which cancer cells harbor the dynamic ability of shifting from a noncsc. Subpopulations of cancer cells with distinct phenotypic and molecular features. Jan 17, 2012 heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. In addition, the role of dedifferentiation of tumor cells into a stem cell like state is discussed as a source of cellular heterogeneity within tumors, highlighting tumor cell plasticity as an important driver of gbm heterogeneity. Comprehensive understanding of cscderived heterogeneity. Breast cancer is a heterogeneous group of neoplasms originating from the epithelial cells lining the milk ducts. The morphological and biomolecular heterogeneity of bc cells, accompanied by dynamic plasticity of the bc microenvironment and the presence of stem like cells, make tumor categorization an urgent and demanding task. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed. The following overview will focus on cancer stem cells and the culture systems for growing and studying these cells. A large body of research indicates that heterogeneity develops through time as tumorinitiating stem cells, also known as cancer stem cells cscs, evolve genetic or epigenetic alterations that allow them to differentiate into multiple tumor cell types.
Hjelmeland1 abstract our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single cell sig. Breast tumor heterogeneity has been noted in histology and clinical outcome for a long time, and these differences have served as the basis for disease classification. Most tumors exhibit intratumor heterogeneity, which is associated with disease progression and an impaired response to therapy. Cell heterogeneity and phenotypic plasticity in metastasis. Understanding cancer stem cell heterogeneity and plasticity nature. Prostate cancer pca has a predominantly luminal phenotype. Stem cell heterogeneity and plasticity in epithelia. Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic andor epigenetic differences amongst the cancer cells themselves. Prasetyanti1,2 and jan paul medema1,2,3 abstract tumor heterogeneity represents an ongoing challenge in the field of cancer therapy.
The role of metabolic plasticity in blood and brain stem cell pathophysiology catherine j. Toward understanding cancer stem cell heterogeneity in the. They examined cancer stem cell plasticity in which cancer stem cells can transition between non cancer stem cells noncsc and csc via in situ supporting a more stochastic model. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in. Pdf cell plasticity and heterogeneity in cancer researchgate. Hcc is clinically, molecularly, and biologically heterogeneous and highly resistant to treatment. Cancer stem cells cscs are a class of pluripotent cells that have been observed in most types of solid and hematologic cancers.
Cscs have been shown in numerous cancer models to be involved in tumor development, cell proliferation, and metastatic dissemination, while possessing a capacity for sustained selfrenewal. Cancer stem cell markers will have to be tested in larger numbers of patients 15,40,65 to account for heterogeneity among patients and to determine whether certain markers are more reliable in certain subsets of patients. One of the most forceful underlying reasons is a cancer heterogeneity due to csc plasticity. Understanding cancer stem cell heterogeneity and plasticity. We find that a spatial gradient of emtinducing signal. Here, i discuss csc heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Sep 18, 20 phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Here, we devise a theoretical framework to investigate how the tumor microenvironment tme modulates this spatial patterning. Changes in stem cell behavior, escape from apoptosis and senescence, ecm and tumormicroenvironment remodeling, and resistance to cytotoxic treatments are only a few among the broad spectrum of downstream emt effectors which contribute to intratumor cell heterogeneity with profound implications for cancer therapeutics, especially in the decade. Commentary open access understanding breast cancer stem cell.
Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drugrefractory cell populations, ultimately leading to therapy failure. Reprogramming to developmental plasticity in cancer stem. Understanding tumor heterogeneity will help design better therapies against gbm and avoid tumor recurrence. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, selfrenewal ability, and tumorinitiating capacity. Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. However one frames this concept, most cancer biologists accept that, at any given time in a cancer, there are populations of cells with cancer cell renewal and tumor initiating properties. Resistance to drugs and cell death in cancer stem cells cscs. It has been recently realized that even mouse and human embryonic stem cells. Request pdf understanding cancer stem cell heterogeneity and plasticty heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. Tumor heterogeneity is a hallmark of cancer and underlies resistance to anticancer therapies and disease progression. Prostate cancer pca is heterogeneous, harboring phenotypically diverse cancer cell types. Tumour heterogeneity and cancer cell plasticity nature.
Revealing the origin of cancer has been a topic of much interest in that it might shed light on a complete treatment of cancer. In many malignancies, this heterogeneity is generated during tumor evolution through a combination of genetic alterations and epigenetic events that recapitulate normal developmental processes including stem cell selfrenewal and differentiation. Inherent to the above concept of cancer cell heterogeneity as it contributes to tumor initiation and progression, is the cancer stem cell hypothesis. B concept that the mechanisms of stem cell plasticity during tissue repair contribute to the evolutionary dynamics of cancer stem cell clones. Frontiers stem cell plasticity and dormancy in the.
About half of human cancers were found to harbor mutations in chromatin proteins. Cell plasticity and heterogeneity in cancer clinical. Key drivers of tumor heterogeneity tumor heterogeneity is generated through a combination of genetic alterations and epigenetic events that abnormally recapitulate normal developmental processes, including stem cell selfrenewal and differentiation. Heterogeneity is evident between cancers from different patients intertumor heterogeneity and within a single tumor intratumor. Prostate luminal cells are understudied compared with basal cells. This will provide insight into whether only certain subtypes or stages of disease follow the cancer stem cell model. Human breast cancer bc is one of the leading causes of death for women worldwide, and is characterized by a group of highly heterogeneous lesions. For the past 20 years, plenty of studies have suggested that only a small subpopulation of the cancer cells with tumorinitiating capability is the core origin of the tumorigenesis and the subset of cancer cells was named cancer stem cells cscs. There are two models used to explain the heterogeneity of tumour cells.
Stem cell heterogeneity and plasticity have been recognized in some wellstudied mammalian tissue stem cells 33. Epigenetic plasticity and the hallmarks of cancer science. According to the plasticity model, intrinsic tumor cell processes andor stimuli within the tumor. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intrapatient heterogeneity. Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating singlecell signatures to explore cellcell interactions and differentiation state. Cancer cell plasticity has been proposed as being an important mechanism that, along with genetic and epigenetic alterations, promotes cancer cell diversity and contributes to intratumor heterogeneity. Cancer stem cells cscs constitute a small subpopulation of cancer cells with stemlike properties that are able to selfrenew, generate differentiated daughter cells, and give rise to heterogeneous tumor tissue. Understanding breast cancer stem cell heterogeneity.
Cell plasticity and how it relates to heterogeneity in cancer. In addition, the role of dedifferentiation of tumor cells into a stem celllike state is discussed as a source of cellular heterogeneity within tumors, highlighting tumor cell plasticity as an important driver of gbm heterogeneity. Commentary open access understanding breast cancer stem cell heterogeneity. Pca cell heterogeneity is caused by genomic instability that leads to the clonal competition and evolution of the cancer genome and by epigenetic mechanisms that result in subclonal cellular differentiation. The second model of cancer stem cell csc or cancerinitiating cell cic theory supports the presence of a specific subpopulation of cancer cells that possess tumorigenic potential and generates tumor cell heterogeneity 20. Cellular plasticity and metastasis in breast cancer. As a first step towards understanding the effect of inflammatory cytokines on notch signaling and the plasticity of tumor cells, we analyzed the. Stem cells are cells with both selfrenewing and differentiation abilities. Heterogeneity in breast cancer kornelia polyak1,2 1department of medical oncology, danafarber cancer institute, brigham and womens hospital, harvard medical school, boston, massachusetts, usa. The second model of cancer stem cell csc or cancer initiating cell cic theory supports the presence of a specific subpopulation of cancer cells that possess tumorigenic potential and generates tumor cell heterogeneity 20. The morphological and biomolecular heterogeneity of bc cells, accompanied by dynamic plasticity of the bc microenvironment and the presence of stemlike cells, make tumor categorization an urgent and demanding task. Importantly, the nature of this heterogeneity is not limited to the malignant cancer cell population only as a tumor is a complex ecosystem containing tumor cells and other cell types, such as endothelial cells, infiltrating immune cells, stromal cells as well as a complex network of extracellular matrix ecm, which defines spatiotemporal.
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