Malignant cells, directors of the malignant process: Role of transforming growth factor-beta

Malignant cells survive and thrive by expressing growth and invasion 'programs' that many normal cell types recognize and respond to in 'programmed' patterns. An early event in the molecular evolution of many malignancies loss of response to growth control by transforming growth factor-beta (TGF-beta) frequently due to mutation in the type I or type II TGF-beta receptor or a Smad protein. The malignant cells secrete TFG-beta that acts on the host to suppress antitumor immune responses, to enhance extracellular matrix production and to augment angiogenesis. These activities resemble those induced by TGF-beta during embryonic development and account in part for the 'de-differentiated' nature of malignant disease. Clinically, TGF-beta1 is often elevated in the plasma of breast cancer patients, lung cancer patients, hepatocellular carcinoma patients, and prostate cancer patients. Preclinically, several breast cancer models and prostate cancer models in vivo have demonstrated a connection between TGF-beta expression and increased tumorigenicity, increased invasion and drug resistance. In other diseases such as colon, gastric, endometrial, ovarian, and cervical cancers and gliomas and melanoma, loss of response to TGF-beta as a growth inhibitor and increased expression of TGF-beta have been associated with malignant conversion and progression. Elevated levels of TGF-beta are measurable in nude mice bearing a wide variety of human tumor xenografts; thus, these tumor models may serve as useful mimics of the human disease with respect to the TGF-beta pathway. Cancer cure may be approached by blocking several of the major normal pathways used for tumor growth and survival in combination with cytotoxic therapies.