No abstract

The growth of cells in 3-dimensional form as nodules in vitro facilitates studies of in vivo cellular interactions. Taking advantage of this technique, human breast carcinoma cells (MCF-7) were co-cultured with stromal fibroblasts isolated from either normal or tumorous breast tissue to study the influence of such fibroblasts on tumor-cell growth and differentiation. Ten days after co-culture of carcinoma cells with fibroblasts from normal tissue at a 1:10 ratio, the size of nodules began to increase and stabilize by day 30 while the fibroblast number decreased and finally disappeared. Concurrently, the carcinoma cells underwent a progressive redifferentiation process which histologically resulted in the appearance of highly developed papillar and tubular structures after 2 months in culture. The production of mucins was further evidence that these cells had undergone differentiation. By contrast, when MCF-7 cells were grown alone or with fibroblasts isolated from a breast carcinoma, the nodules continued to exhibit their characteristic histodedifferentiation properties and did not grow. The re-establishment of a normal epithelial state of differentiation in MCF-7 carcinoma nodules indicates that the phenotypic characteristics of tumor cells are reversible and are influenced or controlled by the stromal environment by which these tumor cells are surrounded or in contact with. Overall, our results open the possibility of exploiting the effects that connective tissue cells have on tumor-cell differentiation for use in prevention and treatment of cancer.

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Cells were isolated from post-radiation fibrosis biopsies of patients with recurrent breast carcinoma. These cells were identified as fibroblasts and compared with fibroblasts from normal breast tissues for their proliferative activities, chromosome number and for the presence of various components of the extracellular matrix and cytoskeleton. The proliferative activity of the fibrosis-derived fibroblasts did not significantly differ from that of normal breast fibroblasts. Both cell types required serum to grow and did not form colonies in soft agar. Cells from 2 of the 3 fibroses analyzed displayed aneuploid karyotypes with multiple structural abnormalities. All of the fibroblastic cells produced types I, III and V collagen, fibronectin and vimentin. However, in contrast to normal breast fibroblasts, fibrosis-derived cells produced high amounts of oncofetal fibronectin. In addition, fibrosis of fibroblasts also expressed the alpha-actin isoform which is specific for smooth-muscle cells. These results suggest that post-radiation fibrosis in malignant breast contains atypical fibroblasts with fetal and myofibroblastic characteristics.

Two new butyric esters which were devised to extend the half-life of n-butyric acid in vivo, were used to study their effects on a number of phenotypic characteristics including cell morphology, cell proliferation, colony formation, cell-surface antigen and estrogen receptor expression in 3 normal immortalized cell lines and 2 carcinoma cell lines derived from the human mammary gland. When treated with butyric esters, human mammary cells acquired numerous cytoplasmic granules and vacuoles, reminiscent of secretory functions, and increased in volume. Modulation of the expression of membrane-associated antigens recognized by the monoclonal antibodies (MAbs) 115D8, 140C1 and 125B5 was also observed. Furthermore, butyrate derivatives inhibited the proliferation of all the cell lines tested and the colony-forming capacity of those that grew in soft agar. The inhibitory effects were, however, reversible upon removal of butyric esters from the culture medium. In the human breast carcinoma cell line, MCF-7, in which the cytostatic effects of butyric esters were the most pronounced, cells accumulated in the G0/G1 phase of the cell cycle. This cell line was the only one to contain estrogen receptors which decreased in number when treated with butyric esters without any modification in their binding affinity. Moreover, the stimulatory effects of estrogen on MCF-7 cell proliferation were antagonized by butyric esters. Our results demonstrate that many of the proliferative and differentiation changes previously reported for n-butyrates in tumor cells are similarly produced by the new stable butyrate derivatives in normal and malignant human mammary cell lines.