Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.

By Selma Pennacchietti, P. Michieli, M. Galluzzo, M. Mazzone, S. Giordano, P. Comoglio. Cancer Cell, 2003

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Hypoxia unleashes the invasive and metastatic potential of tumor cells by largely unknown mechanisms. The Met tyrosine kinase, a high affinity receptor for hepatocyte growth factor (HGF), plays a crucial role in controlling invasive growth and is often overexpressed in cancer. Here we show that: (1) hypoxia activates transcription of the met protooncogene, resulting in higher levels of Met; (2) hypoxic areas of tumors overexpress Met; (3) hypoxia amplifies HGF signaling; (4) hypoxia synergizes with HGF in inducing invasion; (5) the proinvasive effects of hypoxia are mimicked by Met overexpression; and (6) inhibition of Met expression prevents hypoxia-induced invasive growth. These data show that hypoxia promotes tumor invasion by sensitizing cells to HGF stimulation, providing a molecular basis to explain Met overexpression in cancer.

Subfields: Biochemistry, Cancer Research, Surgery

View Paper: https://www.semanticscholar.org/paper/fde8de1a39df6fa5f4099f8290bd39837ba1c622

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Citations in the corpus

Hypoxia and hypoxia-inducible factors (HIFs): master regulators of metastasis (2010, background): “Another mechanism of increasing cell motility is through the activation of MET by HIF-1 (14).”
Targeting cellular metabolism to improve cancer therapeutics (2013, background): “signaling networks to produce similar phenotypic effects in the presence of reduced EGFR family signaling.(112,113) In addition, HIF-1a induces a shift in b-tubulin isoform expres-”
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. (2009, background): “systems (Higgins et al., 2007; Munoz-Najar et al., 2006; Pennacchietti et al., 2003).”
Tumor cell metabolism: cancer's Achilles' heel. (2008, background): “HIF-1a activation also causes the expression of the met proto-oncogene and of TWIST, both of which favor EMT (Pennacchietti et al., 2003; Yang et al., 2008), and induces two proteins that play a cardinal role in metastasis, the chemokine receptor CXCR4 (Igney and Krammer, 2002) and lysyl oxidase (LO”
Cancer metastasis: building a framework. (2006, background): “Prerequisites for Metastasis Tumor-Initiating Capacity Normal cells constitute lineages that extend from stem cells to terminally differentiated progeny.”
New signals from the invasive front (2006, background): “An important example is the hypoxic induction of c- met gene expression, which amplifies HGF signalling by sensitizing cells to HGF signallin”
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Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. (2006, background): “chambers (13, 14) and enhanced lung colonization potential after i.”
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Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. (2005, background): “, 1999, 2000), as well as in other models of cancer (Pennacchietti et al., 2003; Steeg, 2003).”
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