Human breast carcinoma desmoplasia is PDGF initiated.
The desmoplastic response to human breast carcinoma is a host myofibroblast-mediated collagenous response exhibiting synergistic effects on tumor progression. Although many paracrine interactions between breast carcinoma cells and myofibroblasts have been characterized, the event(s) which initiate desmoplasia have remained undefined. Our studies utilized c-rasH transfected MCF-7 cells which overexpress ras p2l and which are weakly tumorigenic in ovariectomized nude mice. The xenografts are desmoplastic and comprised of 30% myofibroblasts and 60 mg/g of interstitial collagen. In situ hybridization studies of these xenografts reveal a stromal gene expression pattern (stromelysin-3, IGF-II and TIMP-1) identical to that observed in human tumor desmoplasia. 17-beta estradiol increases c-rasH MCF-7 growth but abolishes desmoplasia. c-rasH MCF-7 in vitro constitutively produce myofibroblast mitogenic activity which competes with PDGF in a receptor binding assay. This myofibroblast mitogenic activity is unaltered by 17-beta estradiol/tamoxifen pretreatment in vitro. Transfection of c-rasH MCF-7 with a PDGF-A dominant negative mutant, 1308, produced by site-directed mutagenesis (serine-->cysteine129) reduces both homo- and heterodimer secretion of PDGF by as much as 90% but does not interfere with the secretion of other growth factors. Clones with low PDGF, though tumorigenic, are non-desmoplastic. Our results suggest that breast carcinoma-secreted PDGF is the major initiator of tumor desmoplasia.
Shao
Z M
ZM
Department of Pathology, UCLA School of Medicine, Los Angeles, California, CA 90024, USA.
Nguyen
M
M
Barsky
S H
SH
D000818:Animals; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015197:Carcinogenicity Tests; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000187:drug effects / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D010982:Platelet-Derived Growth Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D004958:Estradiol; D007335:Insulin-Like Growth Factor II; D003094:Collagen; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases