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. 2023 Feb 9;15(4):1111. doi: 10.3390/cancers15041111

Figure 2.

Figure 2

Role of hypoxia in the formation of TB. Hypoxia in advanced TME promotes TB development. Genes whose expression is induced by HIF-1α activation by hypoxia promote EMT. YAP is activated in a hypoxic TME and was abrogated by the knockdown of ME1 which promotes the Warburg effect in cancer cells and induces EMT. YAP activation is a significant factor that promotes the EMT phenotype and is deeply involved in the progression of the tumor. In a hypoxic situation, YAP activation is responsible for the upregulation of GPRC5A by binding to HIF-1α. Then, activated YAP also stabilizes HIF-1α and enhances its action. The expression of MMP9 and MMP7 is also upregulated by HIF-1α activation. Moreover, hypoxic TME can induce tumor cells to secrete enhanced amounts of TEVs. The dynamic intercellular crosstalk that is mediated by TEVs mobilizes oncogenic factors, relocalizes CAFs to tumor sites, p-EMT and APT development, and TB formation which sustains cancer progression and metastasis.