Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

Lisa Coussens, Wilfred W. Raymond, Gabriele Bergers, Marion Laig-Webster, Ole Behrendtsen, Zena Werb, George H. Caughey, Douglas Hanahan

Research output: Contribution to journalArticle

727 Citations (Scopus)

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 (KIT(W)/KITW(Wv)) 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.

Original languageEnglish (US)
Pages (from-to)1382-1397
Number of pages16
JournalGenes and Development
Volume13
Issue number11
StatePublished - Jun 1 1999
Externally publishedYes

Fingerprint

Mast Cells
Carcinogenesis
Up-Regulation
Matrix Metalloproteinase 9
Transgenic Mice
Hyperplasia
Neoplasms
Chymases
Tryptases
Skin
Angiogenesis Inducing Agents
Serine Proteases
Matrix Metalloproteinases
Keratinocytes
Mitogens
Basement Membrane
Biological Assay
Squamous Cell Carcinoma
Fibroblasts
Carcinoma

Keywords

  • Angiogenesis
  • Cancer
  • Gelatinase B
  • HPV16
  • Inflammation
  • Mast cells

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Coussens, L., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., ... Hanahan, D. (1999). Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes and Development, 13(11), 1382-1397.

Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. / Coussens, Lisa; Raymond, Wilfred W.; Bergers, Gabriele; Laig-Webster, Marion; Behrendtsen, Ole; Werb, Zena; Caughey, George H.; Hanahan, Douglas.

In: Genes and Development, Vol. 13, No. 11, 01.06.1999, p. 1382-1397.

Research output: Contribution to journalArticle

Coussens, L, Raymond, WW, Bergers, G, Laig-Webster, M, Behrendtsen, O, Werb, Z, Caughey, GH & Hanahan, D 1999, 'Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis', Genes and Development, vol. 13, no. 11, pp. 1382-1397.
Coussens L, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes and Development. 1999 Jun 1;13(11):1382-1397.
Coussens, Lisa ; Raymond, Wilfred W. ; Bergers, Gabriele ; Laig-Webster, Marion ; Behrendtsen, Ole ; Werb, Zena ; Caughey, George H. ; Hanahan, Douglas. / Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. In: Genes and Development. 1999 ; Vol. 13, No. 11. pp. 1382-1397.
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