Cited by 946Angiogenesis and VEGF in CancerMast cells and histamineProtease and Inhibitor Mechanisms

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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

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Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., Hanahan, D.·1999·Genes & Development

DOI 10.1101/gad.13.11.1382PMC PMC316772

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Abstract

Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.

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Authors: Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., & Hanahan, D.
Affiliations: University of California, San Francisco (US)
ORCID: Coussens, L. M.
Bergers, G.
Werb, Z.
Caughey, G. H.
Hanahan, D.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1999-06-01
Volume: 13
Issue: 11
Pages: 1382-1397
ISSN: 0890-9369 (ISSN-L)
DOI: 10.1101/gad.13.11.1382
PMC: PMC316772
OpenAlex: W2146440075
Cited by: 946
References: 87
Citations by year: 2026: 5 · 2025: 14 · 2024: 11 · 2023: 13 · 2022: 27 · 2021: 18 · 2020: 29 · 2019: 31 · 2018: 27 · 2017: 29 · 2016: 39 · 2015: 32 · 2014: 52 · 2013: 32 · 2012: 49
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Pfizer
National Institutes of Health
National Heart, Lung, and Blood Institute (HL 24136, P01HL024136)
National Cancer Institute (CA72006, P01CA072006)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: mast cells, angiogenesis, squamous cell carcinoma, HPV16, keratinocytes, MMP-9, chymase, tryptase, precancerous lesions, dermal fibroblasts, tumor stroma, inflammation, carcinogenesis, neovascularization
MeSH terms: Animals, Carcinoma, Squamous Cell, Extracellular Matrix, Humans, Mast Cells, Mice, Transgenic, Neovascularization, Pathologic, Serine Endopeptidases, Up-Regulation, Inflammation Mediators, Mice, Tryptases, Chymases

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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

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