Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics

Abstract

Epithelial-mesenchymal transition (EMT) has been implicated in various aspects of tumor development, including tumor invasion and metastasis, cancer stemness, and therapy resistance. Diverse stroma cell types along with biochemical and biophysical factors in the tumor microenvironment impinge on the EMT program to impact tumor progression. Here we provide an in-depth review of various tumor microenvironmental signals that regulate EMT in cancer. We discuss the molecular mechanisms underlying the role of EMT in therapy resistance and highlight new therapeutic approaches targeting the tumor microenvironment to impact EMT and tumor progression.

Keywords: Epithelial-Mesenchymal Transition (EMT); Extracellular matrix (ECM); Hypoxia; Invasion and metastasis; Tumor stroma.

Fig. 1.

A summary of various extracellular matrix signals implicated in EMT regulation in the tumor microenvironment. Various ECM molecules, ECM remodeling proteins and physical forces exerted from ECM in the tumor microenvironment activate various biochemical and mechanical signaling pathways to regulate the EMT inducers and EMT transcription factors to drive EMT and tumor progression.

Fig. 2.

A summary of various secreted factors implicated in EMT induction by stromal cells and immune cells. CAFs, CAAs and immune cells including T lymphocytes, TAMs and MDSCs could promote EMT in cancer cells through the secretion of cytokines, chemokines and growth factors, such as TGFβ, IL-6, CXCL12, CCL18, FGF and HGF. Meanwhile, cancer cells secrete various factors to stimulate CAFs or CAAs formation and recruit more Tregs, TAMs or MDSCs. CAFs: cancer associated fibroblasts; CAAs: cancer associated adipocytes; TAMs: tumor associated macrophages; MDSCs: myeloid-derived suppressor cells.

Fig. 3.

A schematic diagram summarizing mechanisms underlying hypoxia-mediated EMT. Hypoxia activates EMT by directly increasing EMT-TFs expression or stimulating various signaling pathways, including TGFβ, Notch, Hedgehog pathway and EGFR pathway. Direct transcription targets, like SNAI1, TGFβ, NOTCH1–1, SHH and EGFR are listed in diagram. Except for HIF-1/2α, ROS could also stimulate EMT by promoting SNAI1 nuclear translocation under hypoxia condition.