Recent studies suggest that fibroblasts from some breast cancer patients differ in culture from fibroblasts from normal individuals. These differences can be seen in peritumor fibroblasts and, in some breast cancer patients, in skin fibroblasts obtained from sites far removed from the malignancy. Among these differences are changes in phenotype often seen with fetal fibroblasts, in particular, changes in patterns of motility. There are indications that these fibroblast abnormalities may even precede the appearance of frank malignancy. These observations imply that cancer of the breast is not a focal disease but is more widespread and, in some, a systemic disorder, and that stromal-epithelial interactions are involved in the genesis and maintenance of breast cancer. Our major objective is to devise assays that measure such differences and thus, could provide important diagnostic markers for women at high risk for developing breast cancer. Our basic hypothesis states that various perturbations of hyaluronic acid metabolism are involved in many of the distinctions so that tumor derived fibroblasts have a higher net level of deposition compared to normal fibroblasts and that such differences are """"""""remembered"""""""" by cells in culture. Hyaluronic acid stimulates cell motility, and its water of hydration opens up tissue space through which cells can move. In several model tumor systems, levels of hyaluronic acid correlate with tumor aggressiveness. In the initial funding period, we identified previously undescribed activities that stimulate and inhibit hyaluronic acid. These hyaluronic acid- modulating activities are cell motility factors and may be part of a family of motility factors involved in stromal-epithelial interactions and cell movement, perturbations of which have been associated with malignant transformation. Characterization of these hyaluronic acid modulating factors and a serum permissive factor, together with the development of rapid assays constitute the major thrust of this project. This will be approached in the following manner: a) documentation of increased levels of hyaluronic acid deposition in tumor-derived fibroblasts compared to normal fibroblasts; b) confirmation that TGFb is involved in that modulation; c) isolation and characterization of hyaluronic acid modulating activities from fibroblast-conditioned media, normal and tumor-derived, using scaled up hollow fiber culture systems; d) demonstration that changes in levels of hyaluronic acid deposition in fibroblasts occur in response to such modulating activities by means of TGFb; e) production of immune reagents that can be utilized in rapid immunoassays, suitable for future population studies; f) examination of other reactions that might be involved in net hyaluronic acid deposition, including hyaluronate synthetase as well as hyaluronidase and its inhibitor. These experiments will increase our understanding of the basic biology of breast cancer and the role host stroma plays in supporting the malignant process, as well as provide important prognostic indicators.
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