Trends in Cell Biology
ReviewEpithelial–Mesenchymal Plasticity: A Central Regulator of Cancer Progression
Section snippets
The EMT is a Naturally Occurring Transdifferentiation Program
The successes over the past decade in reprogramming the terminally differentiated cells of normal adult tissues into pluripotent stem cells 1, 2 have led to the widely embraced assumption that almost any type of dedifferentiation or transdifferentiation is possible, if only the proper combination of ectopically expressed transcription factors is introduced into adult cells. These successes in experimental reprogramming raise the question of which changes in cell state occur in nature rather
The EMT Program and Epithelial–Mesenchymal Plasticity
The EMT program, as its name implies, governs changes of cell states along the epithelial versus mesenchymal axis and converts epithelial cells to mesenchymal cells when this program is fully executed. To describe the extremes poles of the epithelial versus mesenchymal axis (Table 1), one notes that epithelial cells, often with polygonal shapes in monolayer culture, are polarized along their apical-basal axis and are tightly connected to one another laterally via adherens and tight junctions;
EMT and the Normal Epithelial Stem Cell State
Over the past 5 years, a series of discoveries has converged on the conclusion that after epithelial cells pass, at least partially, through an EMT, they are poised to enter into an epithelial stem cell state. At least in the context of mammary epithelial cells, this holds true for both normal and neoplastic cells 10, 11, 12, 13, 14. Given the biological similarities among diverse epithelial cell types [15], it seems plausible that versions of this scenario are likely to hold true in other
EMT and Cancer Pathogenesis
Almost 80% of life-threatening human malignancies derive from epithelial tissues, generating an array of commonly occurring carcinomas, including tumors of the lung, colon, breast, pancreas, prostate, bladder, ovary, kidney, and liver. In each case, the epithelial states of the corresponding normal cells of origin dictate that early-stage tumors arising in these tissues continue to express the cytokeratins and E-cadherin that are hallmarks of the epithelial state. In addition, neoplastic cells
EMT and Entrance into the Cancer Stem Cell State
Cellular heterogeneity has been widely reported in a variety of hematopoietic and solid cancers. One prominent feature of the cellular heterogeneity involves the differing degrees of tumor-initiating potential exhibited by various cancer cells coexisting within the same tumor. These more tumorigenic cells are termed ‘tumor-initiating cells’, or CSCs, because they resemble normal stem cells in terms of the ability to self-renew and generate more differentiated derivatives. The presence of CSCs
Contextual Signals Inducing an EMT in Carcinoma Cells
The patterns of activation of EMTs during development dictate that this program must be expressed in response to contextual signals experienced by individual cells in various locations within developing embryos. By extension, related patterns of heterotypic signaling must also operate during wound healing and tumor progression to activate this program. In certain carcinomas, the expression of EMT programs can often be observed among carcinoma cells that are closely apposed to stromal cells,
EMT, Epithelial–Mesenchymal Plasticity, and the Invasion-Metastasis Cascade
The later stages of malignant progression of carcinomas have been portrayed as a succession of steps termed the ‘invasion-metastasis cascade’ 68, 69. Thus, carcinoma cells within primary tumors acquire invasiveness, intravasate into microvessels within these tumors, circulate to distant anatomical sites (hematogenous dissemination), lodge in microvessels of such distant tissues, invade through the walls of microvessels into the parenchyma of these distant tissues (extravasation), seed the
Concluding Remarks
The connection made between activation of the EMT program and entrance into a CSC state has placed the EMT program as a central regulator of carcinoma progression. Thus, besides the conventional depiction of the EMT program as a driver of metastatic dissemination, activation of the EMT program can directly enhance tumor initiation, thereby creating metastatic CSCs. Moreover, intrinsic epithelial–mesenchymal plasticity enables cancer cells to switch between the mesenchymal CSC state and a more
Acknowledgments
R.A.W. is an American Cancer Society and Ludwig Foundation professor. This research was supported by the Breast Cancer Research Foundation, the Samuel Waxman Cancer Research Foundation, the Ludwig Center for Molecular Oncology at MIT, National Cancer Institute Program P01-CA080111, R01-CA078461, U01-CA184897 (to R.A.W.), K99-CA194160 (to X.Y.), and the Helen Hay Whitney Foundation (to X.Y.).
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