Co-culture with human fibroblasts increases the radiosensitivity of MCF-7 mammary carcinoma cells in collagen gels

The growth and differentiation of normal and neoplastic epithelial cells ma y be regulated by the presence of adjacent normal tissues and cells, partic ularly stromal fibroblasts. However, the influence of normal fibroblast-tum or cell interactions on the response of malignant epithelial cells to radia tion has not been adequately investigated nor has the possible role played by a 3-D environment in such modulation. We addressed this question by embe dding MCF-7 mammary carcinoma cells into a collagen lattice, alone or mixed with HSF human dermal fibroblasts, and kept the gels anchored to the plast ic surface or suspended in the culture medium. Some gels served as controls and others were irradiated with 6 MV photons fractionated into 3 daily dos es totaling 5 or 10 Gy, After 2 or 7 days from the last treatment (7 or 12 days in culture, respectively), gels were processed in I of 2 ways: overall cell survival was determined by the MTT assay, while the survival of MCF-7 cells was selectively detected by a clonogenicity assay. Under these exper imental conditions, we found that, in the presence of HSF fibroblasts, the growth of MCF-7 cells was restrained and radiosensitivity increased compare d with MCF-7 cells cultured alone. For example, while the average number of MCF-7 foci/gel recovered from control gels with MCF-7 cells alone was 2,46 0 on day 7 and 3,290 on day 12 of culture, it was 4 to 5 times lower (p < 0 .001) in control gels with mixed MCF-7 and HSF cells. Radiation affected se verely the survival of MCF-7 cells in all experimental groups but not suffi ciently to mask the differences. For example, following exposure to the low dose of 5 Gy, the average number of MCF-7 foci/gel recovered from MCF-7-co ntaining gels was 590 on day 7 and 329 on day 12 of culture, whereas number s from the gels containing mixed MCF-7 and HSF cells were only 218 and 73, respectively (p < 0.003 in both cases). HSF fibroblasts did not grow in our system, but they contracted strongly anchored and floating gels. (C) 2000 Wiley-Liss, Inc.