Development of TGF-beta resistance during malignant progression

Transforming growth factor-beta (TGF-beta) is the prototypical multifunctio nal cytokine, participating in the regulation of vital cellular activities such as proliferation and differentiation as well as a number of basic phys iological functions. The effects of TGF-beta are critically dependent on th e expression and distribution of a family of TGF-beta receptors, the TGF-be ta types I, II, and III. It is now known that a wide variety of human patho logy can be caused by aberrant expression and function of these receptors. The coding sequence of the type ii receptor (RII) appears to render it uniq uely susceptible to DNA replication errors in the course of normal cell div ision. By virtue of its key role in the regulation of cell proliferation, T GF-beta RII should be considered as a tumor suppressor gene. High levels of mutation in the TGF-beta RII gene have been observed in a wide range of pr imarily epithelial malignancies, including colon and gastric cancer. It app ears likely that mutation of the TGF-beta RII gene may be a very critical s tep in the pathway of carcinogenesis.