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Human breast carcinoma desmoplasia is PDGF initiated

Oncogene volume 19, pages 4337–4345 (2000)Cite this article

Abstract

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-β 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-β 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.

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References

  • Adams EF, Newton CJ, Braunsberg N, Shaikh N, Ghilchik M and James VHT. . 1988 Breast Cancer Res. Treat. 11: 165–172.

  • Arteaga CL and Osborne CK. . 1989 Cancer Res. 49: 6237–6241.

  • Barsky SH and Gopalakrishna R. . 1987a Biochem. Biophys. Res. Commun. 149: 1125–1131.

  • Barsky SH and Gopalakrishna R. . 1987b Cancer Res. 47: 1663–1667.

  • Barsky SH, Green WR, Grotendorst GR and Liotta LA. . 1984 Am. J. Pathol. 115: 329–333.

  • Barsky SH, Sternlicht MD, Safarians S, Nguyen M, Chin K, Stewart SD, Hiti AL and Gray JW. . 1997 Oncogene 15: 2077–2091.

  • Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC and Chambon P. . 1990 Nature 348: 699–704.

  • Bergman I and Loxley R. . 1963 Anal. Chem. 35: 1961–1965.

  • Bronzert DA, Pantazis P, Antoniades N, Kasid A, Davidson N, Dickson RB and Lippman ME. . 1987 Proc. Natl. Acad. Sci. USA 84: 5763–5767.

  • Cullen KJ, Smith HS, Hill S, Rosen N and Lippman ME. . 1991 Cancer Res. 51: 4978–4985.

  • Dickson RB, Kasid A, Huff KK, Bates SE, Knabbe C, Bronzert D, Gelmann EP and Lippman ME. . 1987 Proc. Natl. Acad. Sci. USA 84: 837–841.

  • Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L and Churchill WH. . 1979 J. Natl. Cancer Inst. 62: 1459–1472.

  • Dvorak HF, Dickersin GR, Dvorak AM, Manseau EJ and Pyne K. . 1981a J. Natl. Cancer Inst. 67: 335–345.

  • Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P and Bitzer AM. . 1981b Science 212: 923–924.

  • Goustin AS, Leof EB, Shipley GD and Moses HL. . 1986 Cancer Res. 46: 1015–1029.

  • Hart CE, Bailey M, Curtis DA, Osborn S, Raines E, Ross R and Forstrom JW. . (1990) Biochemistry 29: 166–172.

  • Heldin CH, Westermark B and Wasteson A. . 1981 Proc. Natl. Acad. Sci. USA 78: 3664–3668.

  • Horgan K, Jones DL and Mansel RE. . (1987) Br. J. Surg. 79: 227–229.

  • Kasid A, Lippman ME, Papageorge AG, Lowry DR and Gelmann EP. . (1985) Science 228: 725–728.

  • Lieubeau B, Garrigue L, Barbieux I, Meflah K and Gregoire M. . 1994 Cancer Res. 54: 6526–6532.

  • Malik R, Gope M, Womer RB, Nagashunmugam T, Margolin JF, Basu A and Scher CD. . 1991 Cancer Res. 51: 5626–5631.

  • Manni A, Badger B, Wei L, Zaenglein A, Grove R, Khin S, Heitjan D, Shimasaki S and Ling N. . 1994 Cancer Res. 54: 2934–2942.

  • Mercola M, Deininger PL, Shamah SM, Porter J, Wang C and Stiles CD. . 1990 Genes Dev. 4: 2333–2341.

  • Miura M, Li SW, Dumenil G and Baserga R. . 1994 Cancer Res. 54: 2472–2477.

  • Muschel RJ, Williams JE, Lowy DR and Liotta LA. . 1985 Am. J. Pathol. 121: 1–8.

  • Naundorf H, Fichtner I, Buttner B and Frege J. . (1992) J. Cancer Res. Clin. Oncol. 119: 35–40.

  • Noguchi M, Thomas M, Koyasaki N, Ohta N, Taniya T, Kitagawa H, Miyazaki I and Mizukami Y. . 1993 Mol. Cell. Endocrinol. 92: 69–76.

  • O'Connell JT, Shao ZM, Drori E, Basbaum CB and Barsky SH. . 1998 Hum. Pathol. 29: 1517–1523.

  • Osborne CK and Arteaga CL. . 1990 Breast Cancer Res. Treat. 15: 3–11.

  • Osborne CK, Coronado EB, Kitten LJ, Arteaga CI, Fuqua SAW, Ramasharma K, Marshall M and Li CH. . 1989 Mol. Endocrinol. 3: 1701–1709.

  • Peres R, Betsholtz C, Westermark B and Heldin CH. . 1987 Cancer Res. 47: 3425–3429.

  • Povlsen CO. . 1980 Antibiot. Chemother. 28: 15–28.

  • Prager D, Li HL, Asa S and Melmed S. . 1994 Proc. Natl. Acad. Sci. USA 91: 2181–2185.

  • Shamah SM, Stiles CD and Guha A. . 1993 Mol. Cell. Biol. 13: 7203–7212.

  • Singer C, Rasmussen A, Smith HS, Lippman ME, Lynch HT and Cullen KJ. . 1995 Cancer Res. 55: 2448–2454.

  • Sommers CL, Papageorge A, Wilding G and Gelmann EP. . 1990 Cancer Res. 50: 67–71.

  • Sternlicht MD, Kedeshian P, Shao ZM, Safarians S and Barsky SH. . 1997 Clin. Cancer Res. 3: 1949–1958.

  • Tomlinson J, Barsky SH, Nelson S, Singer S, Pezeshki B, Lee MC, Eilber F and Nguyen M. . 1999 Clin. Cancer Res. 5: 3516–3522.

  • Yee D, Cullen KJ, Paik S, Perdue JF, Hampton B, Schwartz A, Lippman ME and Rosen N. . 1988 Cancer Res. 48: 6691–6696.

  • Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, Lippman ME and Rosen N. . 1989 Mol. Endocrinol. 3: 509–517.

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Acknowledgements

This work was supported by USPHS grants CA40225, CA01351, CA71195 and CA83111, funds from the California Institute for Cancer Research (CICR), the Cancer Research Co-Ordinating Committee (CRCC), and the Jonsson Comprehensive Cancer Center (JCCC).

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Authors and Affiliations

  1. Department of Pathology, UCLA School of Medicine, Los Angeles, 90024, California, CA, USA

    Zhi-Ming Shao & Sanford H Barsky

  2. Department of Surgery UCLA School of Medicine, Los Angeles, 90024, California, CA, USA

    Mai Nguyen

  3. UCLA/Revlon Breast Center, UCLA School of Medicine, Los Angeles, 90024, California, CA, USA

    Mai Nguyen & Sanford H Barsky

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Shao, ZM., Nguyen, M. & Barsky, S. Human breast carcinoma desmoplasia is PDGF initiated. Oncogene 19, 4337–4345 (2000). https://doi.org/10.1038/sj.onc.1203785

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