Resistance to inhibition of cell growth by transforming growth factor-beta and its role in oncogenesis

Transforming growth factor-beta (TGF beta) was first described as a soluble factor capable of transforming normal rat kidney cells in the presence of transforming growth factor-alpha (TGF alpha) or epidermal growth factor (EGF). TGF beta is now known to have a wide spectrum of effects, depending on cell type, culture conditions, and the presence of other growth factors. Whereas picomolar concentrations of TGF beta completely inhibit the growth of most nonmalignant epithelial cells and early hematopoietic progenitor cells, a review of the published English language literature reveals that virtually all malignant cells of epithelial or hematopoietic origin are refractory to the antiproliferative effects of TGF beta in vitro. When compared with normal epithelial cells, malignant carcinoma cells require significantly higher doses of TGF beta to achieve a similar degree of growth suppression or they are only partially suppressed by large doses of TGF beta. This loss of sensitivity to TGF beta is associated with the development of invasive properties. More than one genetic event appears to be required to convert a sensitive cell into one that is completely refractory to TGF beta. In conclusion, resistance to the growth-inhibiting effect of TGF beta appears to be a late but consistent event in the process of malignant transformation in vitro. Identification of the genetic lesions that result in the loss of response to TGF beta may lead to the design of new therapeutic modalities to arrest tumor growth.