STROMAL INFLUENCE ON EXPRESSION OF PRENEOPLASIA

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The theory that carcinogenesis involves both the initiated epithelial cell and its supporting stroma has substantial indirect support from clinical observations and experimental studies but has not yet been well- characterized or understood. For example, carcinoma of the breast, which is a major neoplastic disease of women, often has a strong stromal component but recent data indicate that the abnormal stroma may even precede the development of malignancy in familial breast cancer. Two related hypotheses have been proposed regarding the role of stroma in neoplastic processes in epithelia. On the one hand normal tissue interactions, i.e. interactions between cells, cell types and the extracellular matrix (ECM), may inhibit initiated epithelial cells form expressing the preneoplastic phenotype. Conversely, an abnormal stroma may promote expression of preneoplastic lesions and/or their progression to neoplasia. The proposed studies address the latter hypothesis. The aim of this proposal is to determine the influence of an abnormal stroma on the initiated mammary epithelial cell's capacity to express its altered phenotype. Given the significance of the extracellular milieu in maintaining normal tissue-specific function, the hypothesis that the ECM mediates the interaction between the abnormal stroma and initiated cells will also be examined. Stromal influences on the expression of preneoplasia will be investigated in vivo using cleared murine mammary gland fat pads; the advantage of this is that the distinctive architecture of mammary gland makes it possible to easily separate epithelium from stroma, leaving the fat pad intact for subsequent transplantation of initiated epithelial cells. To establish a model of abnormal stroma the recipient stroma will be irradiated with graded doses of x-rays. Radiation exposure has been shown to induce changes in the quality of both interstitial and basement membrane ECMs. Subsequently, epithelial cells exposed to x-irradiation or the chemical carcinogen 7,12-dimethylbenzanthracene will be transplanted to the fat pad at various times. Epithelial outgrowths in damaged and normal stromal fat pads will be evaluated for the frequency of preneoplastic lesions as characterized by clonal expansion (hyperplasia) or focal lesions that exhibit abnormal cytological characteristics (dysplasia) and their progression to neoplasia. These studies will contrast the patterns of progression and tumorigenesis of chemically and radiation initiated epithelia in the context of an abnormal stroma. The character of the ECM produced by irradiated stroma in vivo, cultured cells and by recombinant tissues will be analyzed using histological, immunochemical and molecular assays. The studies proposed will clarify the role of abnormal stromal- epithelial interactions, mediated possibly through ECM, in mouse mammary gland by providing data on the expression, progression and tumorigenicity of radiation and chemical carcinogen exposed epithelia in an irradiated stroma.