EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity-that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.National Institutes of Health (U.S.) (Grant P01-CA080111

Epithelial–Mesenchymal Plasticity: A Central Regulator of Cancer Progression

The epithelial-mesenchymal transition (EMT) program has emerged as a central driver of tumor malignancy. Moreover, the recently uncovered link between passage through an EMT and acquisition of stem-like properties indicates that activation of the EMT programs serves as a major mechanism for generating cancer stem cells (CSCs); that is, a subpopulation of cancer cells that are responsible for initiating and propagating the disease. In this review, we summarize the evidence supporting the widespread involvement of the EMT program in tumor pathogenesis and attempt to rationalize the connection between the EMT program and acquisition of stem cell traits. We propose that epithelial-mesenchymal plasticity is likely controlled by multiple varients of the core EMT program, and foresee the need to resolve the various programs and the molecular mechanisms that underlie them.Breast Cancer Research FoundationSamuel Waxman Cancer Research FoundationMassachusetts Institute of Technology. Ludwig Center for Cancer ResearchNational Cancer Institute (U.S.).(Program P01-CA080111)National Cancer Institute (U.S.).(Program R01-CA078461)National Cancer Institute (U.S.).(Program U01-CA184897

Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies. Keywords: epithelial-to-mesenchymal transition; cancer; metastasis; cancer stem cellNational Institutes of Health (U.S.) (Grant R01-CA078461

The SUMO guards for SNAIL

The cell-biological program termed epithelial-mesenchymal transition (EMT) plays a key role in adenocarcinoma progression, invasion, and metastasis. An EMT operating within carcinoma cells can be activated by a variety of paracrine signals arising in the tumor microenvironment. These EMT-inducing signals trigger profound transcription changes through activation of EMT-inducing transcription factors (EMT-TFs), leading to repression of genes associated with the epithelial differentiation program and activation of those associated with the mesenchymal program

Hallmarks of Cancer: The Next Generation

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list—reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer

Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells?

Cancer stem cells (CSCs) are similar to normal stem cells in their ability to self-renew and to generate large populations of more differentiated descendants. In contrast to the hierarchical organization that is presumed to be the prevalent mode of normal tissue homeostasis, phenotypic plasticity allows cancer cells to dynamically enter into and exit from stem-cell states. The epithelial-mesenchymal transition (EMT) has been closely associated with the acquisition of both invasive and stem-cell properties in cancer cells. Thereby, EMT programs emerge as important regulators of phenotypic plasticity in cancer cells including their entrance into stem-cell states. Much is still to be learned about the regulation of EMTs through epigenetic mechanisms in cancer cells and the contributions that EMT programs make to normal tissue homeostasis.National Institutes of Health (U.S.) (Grant CA12515)National Cancer Institute (U.S.) (Grant CA12515)National Institutes of Health (U.S.) (Grant DE020817)National Cancer Institute (U.S.) (Grant DE020817

How Does Multistep Tumorigenesis Really Proceed?

Identifying the cancer cells-of-origin is of great interest, as it holds the potential to elucidate biologic mechanisms inherent in the normal cell state that have been co-opted to drive the oncogenic cell state. An emerging concept, proposed here, states that cancer stem cells, key players in cancer initiation and metastasis, arise when transit-amplifying cells with mutant genomes dedifferentiate and enter the stem cell state. This model contrasts with the notion that cancer stem cells are the direct products of neoplastically transformed normal tissue stem cells.National Institutes of Health (U.S.) (grant (P01 CA080111)National Institutes of Health (U.S.) (grant (R01 CA078461

Cancer Cell of Origin: Spotlight on Luminal Progenitors

Does basal type breast cancer arise from oncogenic transformation of a basal cell type? In this issue of Cell Stem Cell, Molyneux et al. (2010) investigate the provenance of the basal-type BRCA1 breast carcinoma and come up with unanticipated results