Hypoxia-induced epithelial to mesenchymal transition in cancer

Abstract

A common feature of many solid tumors is low oxygen conditions due to inadequate blood supply. Hypoxia induces hypoxia inducible factor (HIF) stabilization and downstream signaling. This signaling has pleiotropic roles in cancers, including the promotion of cellular proliferation, changes in metabolism, and induction of angiogenesis. In addition, hypoxia is becoming recognized as an important driver of epithelial-to-mesenchymal (EMT) in cancer. During EMT, epithelial cells lose their typical polarized states and transition to a more mobile mesenchymal phenotype. Hypoxia induces this transition by modulating EMT signaling pathways, inducing EMT transcription factor activity, and regulating miRNA networks. As both hypoxia and EMT modulate the tumor microenvironment (TME) and are associated with immunosuppression, we also explore how these pathways may impact response to immuno-oncology therapeutics.

Keywords: Cancer; EMT; HIF; Hypoxia; Immunosuppression; Metastasis.

Fig. 1:

Hypoxia is a potent driver of EMT, whereby it actively promotes tumor progression and metastasis in part by promoting an immunosuppressive TME. A) Within the cancer cell, hypoxia activates EMT through various pathways. This includes through TGFbeta, NF-kappaB, and Notch signaling, along with EMT-regulating miRNA networks. Activation of these pathways increases expression of several EMT-TFs, which upregulate mesenchymal genes and downregulate epithelial genes. Numerous inhibitors have been discovered to hinder various components of these pathways, including directly blocking HIF activity. B) The hypoxic TME similarly influences EMT of cancer cells. Diverse immune cell types contribute to hypoxia-induced EMT, while also promoting an immunosuppressive environment to avoid detection of the cancer by the immune system.

Fig. 2:

Under low oxygen levels, PHD proteins do not hydroxylate HIFalpha, allowing HIF to accumulate. Active HIF binds to HRE sequences in gene promoters to up-regulate transcription. Several EMT-TFs contain HRE sequences in their promoters, including SNAIL1, TWIST1 and ZEB1. As such, upregulation of HIF in hypoxia promotes EMT. Outside of direct EMT-TF gene activation, HIF upregulates SOX9 and subsequently USP47, which stabilizes SNAIL1 protein by reducing its ubiquitination (Ub).