EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer

By Anurag Singh, J. Settleman. Oncogene, 2010

2,601 citations recorded by the source corpus.

Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-β, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.

Subfields: Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/7ed812dfb641e5e4c51701a11b45da1b271cc9a1

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Citations in the corpus

Hallmarks of cancer: the next generation. (2011, positive): “Increasing evidence in a variety of tumor types suggests that cells with properties of CSCs are more resistant to various commonly used chemotherapeutic treatments (Singh and Settleman, 2010; Creighton et al., 2009; Buck et al., 2007).”
Drug Resistance in Cancer: An Overview (2014, background): “The role of EMT in cancer drug resistance is an emerging area of research [69,70].”
Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes (2012, background): “In the past several years, the epithelial to mesenchymal transition (EMT) and the Wnt (wingless gene) pathways have drawn increasing interest in the areas of developmental biology, cell differentiation, cell cycle, stem cells, cancer progression and treatment, and drug resistance (Lee et al., 2006; ”
Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “Owing to the ability of CSCs to develop chemo- and radioresistance which play key roles in the malignant progression, metastasis, and cancer recurrence, it is suggested that targeting cancer stem cells offers an ultimate goal to overcome a poor prognosis, leading to a better patient survival [15, 22”
MUC1: a multifaceted oncoprotein with a key role in cancer progression. (2014, background): “CSCs have gained remarkable attention in recent years, in part, due to a link with increased recurrence, drug resistance, and metastasis [103].”
Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast (2011, background): “EMT programs activated in carcinoma cells enable them to acquire cellular traits associated with high-grade malignancy, including the ability to complete various steps of the metastatic cascade (Brabletz et al., 2005; Singh and Settleman, 2010).”
The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis (2022, background): “In the later stages of the disease, EMT inhibitors can reduce the proportion of CSCs in tumors, prevent CTC colonization of the primary tumor and reduce the ability of CTCs to generate secondary tumors when seeded at distant sites [278, 304].”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “While EMT and stemness are often considered to be proximal causes of therapy resistance (Holohan et al., 2013; Singh and Settleman, 2010), phenotypic plasticity per se might be the true culprit, by enabling cancer cells to access resistance phenotypes by rewiring of gene regulatory networks (Pisco a”