Mammary Tumor Growth Arrest by Collagen Synthesis Inhibitors

Abstract

The basal lamina is an extracellular matrix material that is deposited by mammary epithelium at the interface between the epithelium and surrounding stroma. It forms a limiting barrier and serves to maintain tissue organization. Recent experiments have indicated that production of the lamina is important for the growth and/or survival of the epithelium of the normal gland and for many well differentiated rate mammary tumors. Lamina deposition can be selectively blocked in vivo by proline analogues that are specific inhibitors of collagen production, with a consequent involution of the mammary epithelium and a regression of mammary tumors. Because of the importance of the lamina, the mechanisms and factors regulating its production have been sought. Current evidence indicates that endogenously produced growth factors regulate lamina production in an autocrine fashion. Very potent factors that differentially stimulate synthesis of the lamina proteins, type IV collagen and laminin, have been detected in rodent and human mammary tumors. Most interestingly, the responsiveness of mammary cells to these growth factors is potentiated when the mammary cells interact with stromal collagen. This seems to provide for the selective deposition of a lamina at the interface between the epithelium and stroma. The dependency of mammary tumors on lamina production can be lost by a process of selection or dedifferentiation. Some rat mammary tumors selected by serial transplantation no longer produce a lamina. Their growth in vivo becomes resistant to proline analogues and their production of the growth factor that enhances lamina protein production is lost. These tumors also do not contain myoepithelial cells, the cells believed to be responsible for most of the type IV collagen production by the normal epithelium and the epithelium of well differentiated mammary tumors.