Growth factors in mechanisms of malignancy: roles for TGF-beta and FGF

Malignant progression is a complex process involving the accumulation of multiple genetic alterations leading to changes in many specialized cell functions. Important in this process is the loss of growth control which is frequently associated with modifications in growth factor production, and growth factor response pathways. Indeed, oncogenes have been characterized that code for polypeptide growth factors or their receptors, and many tumor cell populations release potently mitogenic growth factors which contribute to the malignant properties of tumor cells. In this review, the importance of growth factors in mechanisms of malignant progression is emphasized, using as examples the transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) families. We describe many of the properties and biological activities of these two families of growth factors, focusing on mechanisms of autocrine and intracrine mitogenic stimulation of tumor cell proliferation and malignant progression. The discussion includes evidence for altered growth factor expression in tumor cells, and the relationship between these changes in growth factors and alterations in the regulation of DNA synthesis, cell proliferation, protease production and cell motility required for invasion and metastasis. Recent studies are described that show that aberrant expression of TGF-beta1, bFGF or K-FGF results in dramatic changes in the genetic stability of cells, leading to increased rates of spontaneous gene amplification and the generation of drug resistant variants. These findings describe new malignancy relevant functions for altered growth factor expression.