NATURAL SITE PREFERENCE IN MAMMARY CANCER BIOLOGY

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Mouse mammary tumors demonstrate a preference for growth in their natural anatomic site, the mammary fatpad. Immunological mechanisms do not adequately explain these site effects. We are focusing on the role of intraepithelial and stromal-epithelial cellular interactions. Our first specific aim is to determine the role of soluble factors in the growth interactions. We have developed an assay for diffusible growth factors in which both producer and responder cells grow in a 3-dimensional array in collagen gel matrix. The effect of normal mammary cells on tumor cell and preneoplastic HAN cell growth in this assay accurately reflects in vivo events; that is, both normal mammary epithelium and normal mammary stroma stimulate growth of mammary tumor cells but HAN cells are stimulated only by the stromal cells. Preliminary evidence suggests a reciprocal paracrine interaction in which tumor cells induce an element of normal mammary gland to produce a factor mitogenic for tumor cells. This induction involves a soluble factor produced by the tumor cells. A second specific aim is to determine if normal mammary stroma and epithelium also alter the growth of preneoplastic and neoplastic cells via contact-dependent mechanisms. By utilizing mammary tumor lines with drug resistance markers to study contact-dependent metabolic cooperation between mammary tissues, we have found that tumor cells are as able to communicate as normal mammary or preneoplastic HAN cells, but that tumor cells may be less responsive than normal or preneoplastic cells to regulators of gap junctional communication. A third specific aim is to explore further the possibility that tumor cells are refractory to regulators (coupler and uncouplers) of contact-mediated intercellular communication. Interactive homeostatic processes, which occur between cells from the time of blastula formation, are usually able to maintain tissue integrity throughout life and can be regarded as mechanisms of "non-immune surveillance" against neoplasia. Manipulation of tissue interactions could lead to new therapeutic strategies against cancer growth and progression. Our experimental approaches are based on the principles that cell shape, tissue architecture, extracellular matrix, and stromal- epithelial and intraepithelial interactions may all play significant roles in neoplastic progression as well as in the normal growth and development of the mammary gland.