Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts.
BACKGROUND
The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts.


METHODS
We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells.


RESULTS
Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts.


CONCLUSIONS
Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors.
Samoszuk
Michael
M
Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA. msamoszu@uci.edu
Kanakubo
Emi
E
Chan
John K
JK
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D004396:Coloring Agents / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D012697:Serine Endopeptidases / Q000378:metabolism; D014048:Tolonium Chloride / Q000494:pharmacology; D053802:Tryptases
D004396:Coloring Agents; C496453:FGF7 protein, human; D051523:Fibroblast Growth Factor 7; D014048:Tolonium Chloride; D006493:Heparin; D012697:Serine Endopeptidases; D053802:Tryptases