Intrinsic and Extrinsic Modulators of the Epithelial to Mesenchymal Transition: Driving the Fate of Tumor Microenvironment

Abstract

The epithelial to mesenchymal transition (EMT) is an evolutionarily conserved process. In cancer, EMT can activate biochemical changes in tumor cells that enable the destruction of the cellular polarity, leading to the acquisition of invasive capabilities. EMT regulation can be triggered by intrinsic and extrinsic signaling, allowing the tumor to adapt to the microenvironment demand in the different stages of tumor progression. In concomitance, tumor cells undergoing EMT actively interact with the surrounding tumor microenvironment (TME) constituted by cell components and extracellular matrix as well as cell secretome elements. As a result, the TME is in turn modulated by the EMT process toward an aggressive behavior. The current review presents the intrinsic and extrinsic modulators of EMT and their relationship with the TME, focusing on the non-cell-derived components, such as secreted metabolites, extracellular matrix, as well as extracellular vesicles. Moreover, we explore how these modulators can be suitable targets for anticancer therapy and personalized medicine.

Inhibition to Epithelial-Mesenchymal Transition and Metastatic Potential In Colorectal Cancer Cell By Combination of Traditional Chinese Medicine Formulation Jiedu Sangen Decoction and PD-L1 Inhibitor

“… 36 Among these, multiple invasive and metastatic cancers have been relevant to high level of E-cadherin and low level of N-cadherin, E-cadherin is essential to keep the epithelial phenotype and modulate the balance of the microenvironment through numerous signal pathways, 37 , 38 including Akt/mTOR, 39 Wnt/β-catenin pathways. N-cadherin acts as an indicator of EMT and its expression has been related to the promotion of angiogenesis and vascular homeostasis by stabilizing micro-vessels, 40 and thus suggesting that the loss of E-cadherin and the growthe of N-cadherin have been widely recognized to be EMT-activation molecules. We thus recommend E-cadherin and N-cadherin as key biomarkers to evaluate EMT progress.…”

A Tissue Engineering Approach to Metastatic Colon Cancer

“…The generation of epithelial organoids as a 3D culture system to quickly grow and expand the colonic epithelium obtained from individuals with colon cancer was a breakthrough in in vitro modeling of the colon and facilitated functional studies of human intestinal epithelial cells ( VanDussen et al., 2015 ). However, in both health and disease, the epithelia do not act in isolation and interactively communicate with microenvironmental factors, including the stromal compartment and ECM to maintain epithelial function ( D'Angelo et al., 2020a ; Neal et al., 2018 ). In the past, the ECM had been perceived to be passive.…”

Epigenetic Alterations in Triple-Negative Breast Cancer—The Critical Role of Extracellular Matrix

“…There is growing evidence that altered expression of ECM components induce EMT process and novel ECM/EMT interactions have recently been identified. MMPs are the primary driver of adherens junction degradation, whereas remodeling of actin cytoskeleton is driven by ERM proteins (i.e., ezrin, radixin and moesin) which interact with CD44, a cell surface receptor for hyaluronan (HA) and versican [12]. Cellular interactions with the ECM-associated proteins (SPARC, SERPINE) also activate EMT.…”

“…Cellular interactions with the ECM-associated proteins (SPARC, SERPINE) also activate EMT. Recent evidence suggests that tumor-derived extracellular vesicles (EVs) or EVs secreted by cancer associated fibroblasts (CAFs) in the tumor microenvironment play a fundamental role in triggering EMT, tumor invasion, and metastasis [12]. Mechanical signals from ECM (i.e., rigidity, cell matrix adhesion, cell geometry, and cytoskeletal tension) can also provoke EMT through YAP/TAZ signaling [12].…”

“…HA-CD44 binding also induces CD44 translocation to the nucleus and activation of LOX transcription. LOX, in turn, stimulates the transcription of Twist, a major EMT marker [12]. HA-CD44 interaction is also correlated with the transcription of stem cell markers (Nanog/Oct4/Sox2) as well as microRNA (miR-21, miR-10b, and miR-302) and long non-coding RNA (lncRNA UCA1) signaling [20].…”