The Complexities of TGF-β Action During Mammary and Squamous Cell Carcinogenesis

Erin      C. Connolly; Rosemary      J. Akhurst

doi:10.2174/138920111798808284

Abstract

Many advanced tumors produce excess amounts of Transforming Growth Factor-β (TGF-β), which is a potent growth inhibitor of normal epithelial cells. However, in tumors its homeostatic action on cells can be diverted along several alternative pathways. Thus, TGF-β signaling has been reported to elicit a preventative or tumor suppressive effect during the earlier stages of tumorigenesis, but later in tumor development, when carcinoma cells become refractory to TGF-β-mediated growth inhibition, response to TGF-β signaling elicits predominantly tumor progressing effects. This is not a simple switch from suppression to progression, but more like a rheostat, involving multiple complementary and antagonizing activities that slowly tip the balance from one to the other. This review will focus on the multiple activities of TGF-β in regulation of two epithelial tumor types, namely squamous cell carcinoma and breast cancer. Basic findings in current mouse models of cancer are presented, as well as a discussion of the complicating issue of outcome of altered TGFβ signaling depending on genetic variability between mouse strains. This review also discusses the role TGF-β within the tumor microenvironment particularly its ability to polarize the microenvironment towards a pro-tumorigenic milieu.

Keywords: TGF-β, tumor microenvironment, breast cancer, epithelial cells, pro-tumorigenic milieu, squamous cell carcinoma, epithelial, hematopoietic, immune cells, malignant carcinoma, epithelial to mesenchymal transformation (EMT), multi-stage tumorigenesis model, lymph nodes and lungs, immature state, bone metastasis