Cancer Stem Cells in Squamous Cell Carcinoma Switch between Two Distinct Phenotypes That Are Preferentially Migratory or Proliferative
TL;DR: A need to define therapeutic targets that can eradicate both EMT and self-renewing CSC variants to achieve effective SCC treatment is suggested.
Abstract: Epithelial-to-mesenchymal transition (EMT) is an important driver of tumor invasion and metastasis, which causes many cancer deaths. Cancer stem cells (CSC) that maintain and initiate tumors have also been implicated in invasion and metastasis, but whether EMT is an important contributor to CSC function is unclear. In this study, we investigated whether a population of CSCs that have undergone EMT (EMT CSCs) exists in squamous cell carcinoma (SCC). We also determined whether a separate population of CSCs that retain epithelial characteristics (non-EMT CSCs) is also present. Our studies revealed that self-renewing CSCs in SCC include two biologically-distinct phenotypes. One phenotype, termed CD44(high)ESA(high), was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44(high)ESA(low), was migratory and had mesenchymal traits characteristic of EMT CSCs. We found that non-EMT and EMT CSCs could switch their epithelial or mesenchymal traits to reconstitute the cellular heterogeneity which was characteristic of CSCs. However, the ability of EMT CSCs to switch to non-EMT character was restricted to cells that were also ALDH1(+), implying that only ALDH1(+) EMT cells had the ability to seed a new epithelial tumor. Taken together, our findings highlight the identification of two distinct CSC phenotypes and suggest a need to define therapeutic targets that can eradicate both of these variants to achieve effective SCC treatment.
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TL;DR: The role of the transcriptional and epigenetic landscapes, gene regulatory network and their surrounding niche in controlling the transition through the different EMT states in cancer is summarized.
1,430 citations
TL;DR: The results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis, at least in human melanoma- and breast cancer-derived tumours.
Abstract: The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
895 citations
TL;DR: It is proposed that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
Abstract: Previous studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24−CD44+ are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
843 citations
Cites background from "Cancer Stem Cells in Squamous Cell ..."
...Several recent studies that demonstrated the importance of cellular plasticity in metastasis support such a model (Biddle et al., 2011; Thompson and Haviv, 2011)....
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TL;DR: It became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective and that immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
Abstract: Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
802 citations
TL;DR: The operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M are reviewed and a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity is presented.
Abstract: Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes – epithelial and mesenchymal, cells can also attain a hybrid epithelial/ mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (eg. adhesion) and mesenchymal (eg. migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor Cells (CTCs). If these clusters enter the circulation, they can be more apoptosis-resistant and more capable of initiating metastatic lesions than cancer cells moving individually with wholly mesenchymal phenotypes, having undergone a complete EMT. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a ‘three-way’ switch giving rise to three distinct phenotypes – epithelial, mesenchymal and hybrid epithelial/mesenchymal. We further characterize this hybrid E/M phenotype in terms of its capabilities in terms of collective cell migration, tumor-initiation, cell-cell communication, and drug resistance. We elucidate how the highly interconnected coupling between these modules coordinates cell-fate decisions among a population of cancer cells in the dynamic tumor, hence facilitating tumor-stroma interactions, formation of CTC clusters, and consequently cancer metastasis. Finally, we discuss the multiple advantages that the hybrid epithelial/mesenchymal phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary ‘bad actors’ of metastasis.
554 citations
Cites background from "Cancer Stem Cells in Squamous Cell ..."
...An alternative hypothesis that attempts to resolve the connection between EMT, MET, and stemness proposes that CSCs come in two distinct states – “epithelial-like” and “mesenchymal-like” (151, 152)....
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...(152), thereby contributing to the notion that cells locked in a complete EMT phenotype significantly lose their plasticity....
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...(152)) can give rise to both epitheliallike and mesenchymal-like populations and hence bilineage colonies in vitro....
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References
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TL;DR: The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival and strategies designed to target this population may lead to more effective therapies.
Abstract: Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.
10,058 citations
"Cancer Stem Cells in Squamous Cell ..." refers background in this paper
...For solid tumors, CSCs with these properties were first shown in breast cancers as cells with a CD44highCD24lowESAþ staining pattern (6)....
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TL;DR: It is reported that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers, and it is shown that those cells have an increased ability to form mammospheres, a property associated with mammARY epithelial stem cells.
8,052 citations
"Cancer Stem Cells in Squamous Cell ..." refers background in this paper
...Breast-cancer cells with the CD44highCD24low tumor-initiating phenotype express EMT markers, a finding that established a link between CSCs and EMT (16) and it is now increasingly recognized that EMT plays an important role in the metastasis of OSCC (15), breast cancer (17), and several other types of carcinoma....
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...Breast cancer cells with the CD44CD24 tumour-initiating phenotype express EMT markers, a finding that established a link between CSCs and EMT (16) and it is now increasingly recognized that EMT plays an important role in the metastasis of OSCC (15), breast cancer (17), and several other types of carcinoma....
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Journal Article•
TL;DR: The identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation is reported.
Abstract: Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.
4,899 citations
"Cancer Stem Cells in Squamous Cell ..." refers methods in this paper
...As ability to grow as floating spheres is a characteristic of CSCs in breast (29) and brain tumors (30), we counted the number of spheres formed when the three populations were seeded in suspension culture using nonadherent plates (Fig....
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TL;DR: It is shown that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties and these cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model.
3,766 citations
TL;DR: A mechanistic link between Twist, EMT, and tumor metastasis is established, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT).
3,670 citations
"Cancer Stem Cells in Squamous Cell ..." refers background in this paper
...tion of epithelial products such as E-cadherin and upregulation of EMT-inducing transcription factors, such as Twist and Snail (11, 12)....
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...In Met2, the CD44highESAlow cells also have greater expression for Twist, Snail, and Axl, perhaps suggesting that they have undergone a more complete EMT than the corresponding population in Met1....
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...1G) that the CD44highESAlow cells have greater expression of Vimentin, Twist, Snail, and Axl, all markers of EMT, and lower expression of the epithelial-specific genes E-cadherin, Calgranulin B, Involucrin, and Keratin 15....
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...In adult tissues, several stromal signals including TGF-b can induce EMT and lead to downregulation of epithelial products such as E-cadherin and upregulation of EMT-inducing transcription factors, such as Twist and Snail (11, 12)....
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