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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Open accessAbstract
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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“Genetic and functional experiments indicate that neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines11,23–26.”
From Inflammation and cancer (2002) · cites this paper as [24]
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The metastasis-promoting roles of tumor-associated immune cells
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Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/−- and c-kit-Dependent Bone Marrow
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Mast cells in atopic dermatitis
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“Current Opinion in Immunology 2009, 21:666–678 autoimmune diseases [8,9], allograft tolerance [10], angiogenesis in tissue repair [11], and carcinogenesis [12,13].”
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Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer
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“For example, MMP-7 and -9 may both induce tumor angiogenesis or inhibit it by generation of angiostatin (48,109,179).”
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Cytokines as a key component of cancer-related inflammation
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Tumor-Host Interactions: A Far-Reaching Relationship
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Immune escape as a fundamental trait of cancer: focus on IDO
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“, 2006) may serve an important role in epithelial tumorigenesis (Coussens et al., 1999; Muto et al., 2007; Soucek et al., 2007).”
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Cancer and Inflammation: Promise for Biologic Therapy
Demaria, S., Pikarsky, E., Karin, M., Coussens, L. M., Chen, Y., El-Omar, E. M., Trinchieri, G., Dubinett, S. M., Mao, J. T., Szabo, E. M., et al. (2010) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181d32e74 · Cited by 336
“Preclinical data suggest that they contribute to tumor progression, perhaps by promoting angiogenesis.(15,16) However, clinical data are contradictory showing association of mast cell numbers with poor survival in some studies, and with improved survival in others.”
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Are Mast Cells MASTers in Cancer?
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“Skin Chloroacetate esterase/hematoxylin (98)”
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Stromal cells can contribute oncogenic signals
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Stromal biology of pancreatic cancer
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“As in a mouse model of squamous epithelial carcinogenesis [Bergers et al., 1998; Coussens et al., 1999, 2000; Hoffman et al., 2003], one might speculate that the stroma around the in situ PanINs may promote tumor growth, angiogenesis, ECM remodeling, and assist in tumor invasion, although a neutral…”
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RetractedThree-dimensional context regulation of metastasis
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B Cells Regulate Macrophage Phenotype and Response to Chemotherapy in Squamous Carcinomas
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“…of multistage epithelial carcinogenesis where HPV16 early region genes are expressed under control of a K14 promoter, i.e., K14-HPV16 mice (Arbeit et al., 1994; Coussens et al., 1996, 1999,2000; Daniel et al., 2003; de Visser et al., 2004, 2005; Rhee et al., 2004; van Kempen et al., 2002).”
Self-citation
Metadata
- 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)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-06-01
- Volume
- 13
- Issue
- 11
- Pages
- 1382-1397
- ISSN
- 0890-9369 (ISSN-L)
- 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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