HIF-1α Mediates Tumor Hypoxia to Confer a Perpetual Mesenchymal Phenotype for Malignant ProgressionA presentation from the Keystone Symposium on Epithelial Plasticity and Epithelial-to-Mesenchymal Transition, Vancouver, British Columbia, Canada, 21 to 26 January 2011.

Abstract

Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1α function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT that requires the transcription factor Twist1. Moreover, we show that the perpetual EMT driven by chronic hypoxia depends on HIF-1α induction of genetic alterations rather than its canonical transcriptional activator function. These mesenchymal tumor cells not only acquire tumorigenicity but also display characteristics of advanced cancers, including necrosis, aggressive invasion, and metastasis. Hence, these results reveal a mechanism by which HIF-1α promotes a perpetual mesenchymal phenotype, thereby advancing tumor progression.

Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition

“…Both hypoxia (15,16) and antiangiogenic therapy (17,18) is known to promote EMT in several epithelial tumor types. Hypoxia likely contributes to both the inflammatory microenvironment and directly or indirectly promotes mesenchymal changes.…”

“…BMDCs, especially CD11bþ/Gr1þ myeloid cells, have been associated with refractoriness to anti-VEGF therapy (14). Both hypoxia (15,16) and antiangiogenic therapies (17,18) are known to promote epithelial to mesenchymal transformation (EMT) in several epithelial tumor types. Therefore, we hypothesized that antiangiogenic therapy may be inducing a highly inflammatory environment and creating resistance by promoting a proneural to mesenchymal phenotypic shift.…”

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

“…Also, hypoxia inducible factor (HIF) α regulates transcriptional regulators of EMT such as Twist (32)and ZEB1 (33)(34)(35). In several cancer cell lines, N-cadherin, vimentin and fibronectin are upregulated in hypoxia exposure (32).…”

Autophagy Inhibition Sensitizes Colon Cancer Cells to Antiangiogenic and Cytotoxic Therapy

“…The degree to which hypoxia is induced in different models is similar: the production of tumor shrinkage by bevacizumab, however, depends on susceptibility to hypoxiainduced cell death (11). An emerging concern with antiangiogenic therapy is that under this selection pressure, more aggressive tumor behavior may ensue (12,13). Furthermore, cells in hypoxic environments have been shown to accumulate mutations and more aggressive growth characteristics (14,15).…”