Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

Abstract

SummaryThe oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor b (TGF-b) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

“…Because there is a strong link between EMT and drug resistance (32), it is possible that phosphorylation and inactivation of YAP by Cdk1 may compromise its ability to trans-activate another transcription factor that suppresses E-cadherin and induces EMT. Moreover, because EMT plays important roles in stem cell renewal, cell migration, anoikis, invasion, and metastasis (33,34), it will be also interesting to further explore how phosphorylation of YAP under physiologic condition regulates these important biologic processes.…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…139 Resistance to cell death is indeed an important feature not only during the process of EMT, but also for the generation of CSCs. 140 Based on a variety of findings, it could be argued that EMT and changes in differentiation induce stem like properties in cancer cells, as opposed to the hypothesis of CSCs being derived from malignant transformation of stem-like progenitor cell types in the mammary gland.…”

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

“…EMT is a process with fundamental molecular change and architectural rearrangement, which causes phenotypic transition of epithelial cells to mesenchymal cells. This transition increases the cellular capacity for migration and invasion and confers resistance to anoikis [3][4][5]. Interestingly, the process of EMT is already operative within days of conception and during embryonic implantation [6].…”