Summary
In the mammary gland, mesenchymal-epithelial interactions are of paramount importance during normal and tumoral developments. We have studied the paracrine growth regulation of a variety of breast epithelial cells in coculture with normal or pathological breast fibroblasts. Two models of coculture were used in which the two cell types were seeded and grown, either together in microchamber slides or separated by a microporous membrane. Under these two conditions, all fibroblasts were shown to stimulate the proliferation of the hormono-responsive breast carcinoma MCF-7 cell line, suggesting that cell contacts were not indispensable for the paracrine stimulation of MCF-7 cell growth by fibroblasts. Moreover, in the Transwell coculture system, the proliferation of a variety of other breast carcinoma cells (MDA-MB231, T47D, and BT-20) was also stimulated by fibroblasts. However, the amplitude of the proliferative response seemed to be dependent on the carcinoma cell line considered. Moreover, the proliferative response of normal mammary epithelial cells to the presence of fibroblasts was shown to be significantly higher than the tumor cell response. The nature of the tissue of fibroblast origin, normal or pathological, did not influence the growth response of the epithelial cells. In this study, we thus demonstrate that fibroblasts are able to stimulate the proliferation of normal and carcinoma cells through paracrine exchange mechanisms. We also conclude that the target epithelial cell phenotype will essentially determine the extent of the proliferative response.
Similar content being viewed by others
References
Adam, L.; Crépin, M.; Lelong, J. C., et al. Selective interactions between mammary epithelial cells and fibroblasts in co-cultures. Int. J. Cancer 59:262–268; 1994.
Adams, E. F.; Newton, C. J.; Braunsberg, H., et al. Effects of human breast fibroblasts on growth and 17β-estradiol dehydrogenase activity of MCF-7 cells in culture. Breast Cancer Res. Treat. 11:165–172; 1988.
Brouty-Boyé, D.; Mainguene, C.; Magnien, V., et al. Fibroblast-mediated differentiation in human breast carcinoma cells (MCF-7) grown as nodules in vitro. Int. J. Cancer 56:731–735; 1994.
Byers, S.; Park, M.; Sommers, C., et al. Breast carcinoma: a collective disorder. Breast Cancer Res. Treat. 31:203–215; 1994.
Camps, J. L.; Chang, S. M.; Hsu, T. C., et al. Fibroblast mediated acceleration of human epithelial tumor growth in vivo. Proc. Natl. Acad. Sci. USA 87:75–79; 1990.
Clarke, R.; Dickson, R. B.; Lippman, M. E. Hormonal aspects of breast cancer. Growth factors, drugs and stomal interactions. Crit. Rev. Oncol. Hematol. 12:1–23; 1992.
Cunha, G. R. Role of mesenchymal-epithelial interactions in normal and abnormal development of mammary gland and prostate. Cancer Suppl. 74:1030–1044; 1994.
Ellis, M. J. C.; Singer, C.; Hornby, A., et al. Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res. Treat. 31:249–261; 1994.
Enami, J.; Enami, S.; Koga, M. Growth of normal and neoplastic mouse mammary epithelial cells in primary culture: stimulation by conditioned medium from mouse mammary fibroblasts. Gann 74:845; 1983.
Haslam, S. Z. Mammary fibroblasts influence on normal mouse epithelial cell responses to estrogen in vitro. Cancer Res. 46:310–316; 1986.
Hofland, L. J.; van der Burg, B.; van Eijck, C. H. J., et al. Role of tumor derived fibroblasts in the growth of primary cultures of human breast-cancer cells: effects of epidermal growth factor and the somatostatin analogue octreotide. Int. J. Cancer 60:93–99; 1995.
Horgan, K.; Jones, D. L.; Mansel, R. E. Mitogenicity of human fibroblasts in vivo for human breast cancer cells. Br. J. Surg. 74:227–229; 1987.
Lefebvre, M. F.; Guillot, C.; Crépin, M., et al. Influence of tumor derived fibroblasts and 1,25-dihydroxyvitamin D3 or growth of breast cancer cell lines. Negative regulation by 1;25-dihydroxyvitamin D3. Breast Cancer Res. Treat. 33:189–197; 1995.
Liu, J.; Bagheri-Yarmand, R.; Xia, Y., et al. Modulations of breast fibroblast and carcinoma cell interactions by a dextran derivative (CMDB7). Anticancer Res. 17:253–258; 1997.
McGraph, C. M. Augmentation of the response of normal mammary epithelial cells to estradiol by mammary stroma. Cancer Res. 43:1355–1360; 1983.
Mukaida, H.; Hirabayashi, N.; Hirai, T., et al. Significance of freshly cultured fibroblasts from different tissues in promoting cancer cell growth. Int. J. Cancer 48:423–427; 1991.
Noël, A.; Munaut, C.; Boulvain, A., et al. Modulation of collagen and fibronectin synthesis in fibroblasts by normal and malignant cells. J. Cell. Biochem. 48:150–161; 1992.
Noël, A.; De Pauw-Gillet, M. C.; Purnell, G., et al. Enhancement of tumorigenicity of human breast adenocarcinoma cells in nude mice by matrigel and fibroblasts. Br. J. Cancer 68:909–915; 1993.
Orr, D. J. A.; Ryan, M. C.; Horgan, K. Demonstration of a positive feedback loop of paracrine growth stimulation in a new co-culture model of breast cancer. Breast 2:138–143; 1993.
Ryan, M. C.; Orr, D. J. A.; Horgan, K. Fibroblast stimulation of breast cancer cell growth in a serum-free system. Br. J. Cancer. 67:1268–1273; 1993.
Singer, C.; Rasmussen, A.; Smith, H. S., et al. Malignant breast epithelium selects for insulinlike growth factor II expression in breast stroma: evidence for paracrine function. Cancer Res. 55:2448–2454; 1995.
van den Hooff, A. Stromal involvement in malignant growth. Adv. Cancer Res. 50:159–196; 1988.
van Roozendaal, C. E. P.; van Ooijen, B.; Klijn, J. G. M., et al. Stromal influence on breast cancer cell growth. Br. J. Cancer 65:6691–6696; 1992.
van Roozendaal, C. E. P.; Klijn, J. G. M.; van Ooijen, B., et al. Differential regulation of breast tumor cell proliferation by stromal fibroblasts of various breast tissue sources. Int. J. Cancer 65:120–125; 1996.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gache, C., Berthois, Y., Martin, PM. et al. Positive regulation of normal and tumoral mammary epithelial cell proliferation by fibroblasts in coculture. In Vitro Cell.Dev.Biol.-Animal 34, 347–351 (1998). https://doi.org/10.1007/s11626-998-0012-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11626-998-0012-2