Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction

Reciprocal interactions between epithelium and mesenchyme mediate crucial aspects of embryonic development and direct the coordinated organogenesis, correct spatial orientation, and the timely expression of functional activity consistent with physiological demands. The mesenchymal equivalent in the adult organism is the stroma, i.e., the loose connective tissue that is separated from the epithelial compartment by an intact basement membrane. In carcinomas, the cellular organization is dramatically changed, and the stroma is extensively modified. The basement membrane is penetrated in a process of degradation and/or decreased synthesis, and direct contact between tumor cells and the surrounding stroma coincides with neovascularization, inflammatory cell influx, and extensive remodeling of extracellular matrix. In this review, we highlight our current knowledge of tumor cell stromal interactions in the mammary gland with particular emphasis on cellular origins and functional phenotypes. We focus both on normal mammary gland and breast tumors and on culture systems developed to dissect individual aspects of cell-cell and cell-extracellular matrix interactions.