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.

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

PENNACCHIETTI, Selma;MICHIELI, Paolo;M. MAZZONE;GIORDANO, Silvia;COMOGLIO, Paolo
2003

Abstract

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.
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S. PENNACCHIETTI; P. MICHIELI; M. GALLUZZO; M. MAZZONE; S. GIORDANO; P. COMOGLIO
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/39201
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