Positive regulation of normal and tumoral mammary epithelial cell proliferation by fibroblasts in coculture

Abstract

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.

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

“…7 Multiple studies have demonstrated that CAFs have a stronger growth-promoting effect on normal or cancerous breast epithelial cells than NAFs. [31][32][33][34][35][36] Overall, these previous results support our findings indicating that NAFs inhibit the growth of normal or hyperplastic epithelium, but are, in general, less able to alter the growth of cancer epithelial cells.…”

Breast fibroblasts modulate epithelial cell proliferation in three-dimensional in vitro co-culture

“…One of several possible explanations for this discrepancy between the prior result and the present result is a difference in E:F. Shekhar and colleagues used an E:F of 1:1 rather than the E:F of 2:1 we initially used [22]. The number of fibroblasts has been shown to have an effect on the response of epithelial cells [7,9,14]. We therefore repeated the 3D co-cultures of MCF10A cells using NAF-2 and CAF-1 with increasing numbers of fibroblasts (i.e.…”

“…In most in vitro analyses, however, direct and indirect co-culture with CAF increased the growth of MCF-7 breast cancer cells compared with MCF-7 cells alone [7,12,14,38]. Co-culture of NAF with MCF-7 cells caused both growth promotion [7,10,11,13,39,40] and inhibition [8] of MCF-7 cells. In contrast, co-culture of NAF and CAF with the breast cancer cell line MDA-MB-231 had no significant effect on epithelial cell growth [10,11].…”

“…It is theorized that CAF act to enhance breast cancer progression [2], and much of the experimental evidence to date supports this contention [7-14]. However, assessment of the effect of CAF has concentrated on established breast cancers.…”

Categorization of Mammographic Density for Breast Cancer

“…The mammographically dense area is composed of both stromal and epithelial tissue. Several studies have shown that the stroma can provide a microenvironment that promotes tumor growth, invasion, and metastasis as a result of the interaction between the stroma and breast cancer (van Roozendaal et aL, 1992;Gache et al, 1998;Noel and Foidart, 1998). Epidemiological surveys have already shown that increased breast density is an independent risk factor for breast cancer Harvey and Bovbjerg, 2004).…”