Epithelial-Mesenchymal Transition in Tumor Microenvironment Induced by Hypoxia

A tumor microenvironment contains various noncancerous cells including adipocytes, fibroblasts, immune and inflammatory cells, neuroendocrine cells, pericytes, vascular and lymphatic endothelial cells, and the extracellular matrix that surrounds cancerous cells. In the tumor microenvironment, cancer cells interact and cross talk with noncancerous cells and orchestrate different mechanisms of cancer such as tumorigenesis, angiogenesis, and metastasis. Moreover, the expansive nature of cancer cells and chaotic angiogenesis affect microcirculation as well as alter the oxygen concentration progres - sively. Hypoxia, a key player in the multistep process of cancer metastasis, is important in different regions of the tumor microenvironment. Hypoxia may transform cancer cells to become more aggressive and invasive by triggering overexpression of several hypoxia-related factors that activate epithelial-mesenchymal transition (EMT). Herein, the current knowledge of how hypoxia-driven EMT is presented in the tumor microenvironment of solid cancers is discussed. EMT and CSC-like properties including resistance to treatment. Each step of the cancer adap tive process is regulated by HIF, NFĸB, PI3K, and MAPK pathways. Understanding the impact of hypoxia and clarifying the hypoxia-induced responses and signaling modalities may pave the way to achieve important steps against cancer via hypoxia/HIF-targeted treatments.