Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene
Open accessAbstract
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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Hypoxia and HIFs can induce tumor cell invasion and degradation of the extracellular matrix via mechanisms including upregulation of cathepsin D, urokinase-type plasminogen activator receptor, and matrix metalloproteinases-1 and -2 and activation of Met.
“Hypoxia and HIFs can also induce tumor cell invasion and degradation of the extracellular matrix via various mechanisms including upregulation of cathepsin D, urokinase-type plasminogen activator receptor, and matrix metalloproteinases-1 and -2 (Krishnamachary et al., 2003;Munoz-Najar et al., 2006) and activation of Met (Pennacchietti et al., 2003).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Pennacchietti et al., 2003
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- Authors
- Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M.
- Affiliations
- University of Turin (IT)
- Corresponding author
- Michieli, Paolo
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 3
- Issue
- 4
- Pages
- 347-361
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2054633892
- Cited by
- 1,311
- References
- 5
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 22 · 2023: 46 · 2022: 39 · 2021: 61 · 2020: 54 · 2019: 27 · 2018: 46 · 2017: 69 · 2016: 73 · 2015: 80 · 2014: 65 · 2013: 70 · 2012: 77
- FWCI
- 23.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Giovanni Armenise-Harvard Foundation
- Ministerio de Economía y Competitividad
- Associazione Italiana per la Ricerca sul Cancro
- Australasian Society for Human Biology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- hypoxia, hepatocyte growth factor, tumor invasion, metastasis, transcriptional activation, HGF signaling, tumor hypoxia
- MeSH terms
- Hypoxia, Base Sequence, Cell Movement, Cells, Cultured, Fluorescent Antibody Technique, Humans, Molecular Sequence Data, Neoplasm Invasiveness, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Tumor Cells, Cultured, Blotting, Northern, Blotting, Western, Hepatocyte Growth Factor, Gene Transfer Techniques, Proto-Oncogene Proteins c-met
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