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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis.
L M Coussens1, W W Raymond, G Bergers
1Hormone Research Institute, University of California, San Francisco. San Francisco, California 94143-0534, USA. coussens@cc.ucsf.edu
Genes & Development
|June 11, 1999
Summary
Mast cells drive angiogenesis in premalignant lesions by releasing proteases that activate matrix metalloproteinase MMP-9. This inflammatory response is crucial for squamous cell carcinoma development in HPV16 transgenic mice.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Squamous cell carcinoma (SCC) development involves complex interactions between tumor cells and the microenvironment.
- Human papillomavirus type 16 (HPV16) early region genes drive a multistage pathway to SCC in transgenic mouse models.
- Angiogenesis, the formation of new blood vessels, is critical for tumor growth and metastasis.
Purpose of the Study:
- To investigate the role of mast cells and matrix metalloproteinase MMP-9 in angiogenesis during HPV16-induced squamous carcinogenesis.
- To elucidate the mechanisms by which mast cell proteases contribute to stromal remodeling and neovascularization.
- To determine the impact of mast cell deficiency on premalignant angiogenesis and tumor progression.
Main Methods:
- Analysis of mast cell infiltration and degranulation in premalignant lesions and carcinomas of HPV16 transgenic mice.
- Assessment of matrix metalloproteinase MMP-9/gelatinase B activation.
- In vitro bioassays to evaluate the angiogenic potential of mast cell proteases MCP-4 and MCP-6.
- Comparison of angiogenesis in HPV16 transgenic mice with and without mast cells (KITW/KITWWv).
Main Results:
- Mast cell infiltration and MMP-9 activation correlate with the angiogenic switch in premalignant lesions.
- Mast cell proteases MCP-4 (chymase) and MCP-6 (tryptase) are released near capillaries and basement membranes.
- MCP-6 promotes fibroblast proliferation, while MCP-4 activates progelatinase B and induces angiogenesis in hyperplastic skin.
- Premalignant angiogenesis is significantly reduced in mast-cell-deficient HPV16 transgenic mice.
Conclusions:
- Neoplastic progression in this SCC model involves the exploitation of inflammatory responses mediated by mast cells.
- Mast cells are recruited to reorganize the stroma and promote angiogenesis at invasive fronts of premalignant lesions.
- Tumor cells within the cancer core appear to sustain neovascularization independently of mast cells, suggesting a biphasic regulation of angiogenesis.