Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

Expression of HPV16 early region genes in basal keratinocytes of transgenic mise elicits a multistage pathway to squamous carcinoma. We report that in filtration by mast cells and activation of the matrix metalloproteinase MMP -9/gelatinase B coincides with the angiogenic switch in premalignant lesion s. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of c arcinomas, but not the core of solid turners, where they degranulate in clo se apposition to capillaries and epithelial basement membranes, releasing m ast-cell-specific serine proteases MCP-C (chymase) and MCP-6 (tryptase). MC P-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 hyp erplastic skin to become angiogenic in an in vitro bioassay. Notably, prema lignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this mo del involves exploitation of an inflammatory response to tissue abnormality . Thus, regulation of angiogenesis during squamous carcinogenesis is biphas ic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory m ast cells are conscripted to reorganize stromal architecture and hyperactiv ate angiogenesis; within the cancer core, upregulation of angiogenesis fact ors in tumor cells apparently renders them self-sufficient at sustaining ne ovascularization.