Growth Factors and Cancer

Summary and Conclusions

Growth factors, defined as polypeptides that stimulate cell proliferation, are major growth-regulatory molecules for cells in culture and probably also for cells in vivo. Nontransformed cells show an absolute requirement for growth factors for proliferation in culture and generally more than one growth factor is required. Under usual culture conditions, growth factors are more rapidly depleted than other media components and thus become rate limiting for proliferation. The loss of or decreased requirement for specific growth factors is a common occurrence in neoplastically transformed cells and may lead to a growth advantage, a cardinal feature of cancer cells. Recent work with transforming growth factors, the platelet-derived growth factor, and oncogenes has produced some insight into the mechanisms through which alterations in growth factor-receptor-response pathways could lead to a growth advantage. Evidence has been derived for autocrine secretion in which the cell produces its own growth factor. Many transformed mesenchymal cells produce PDGF (the product of the c-sis proto-oncogene) and certain transformed cells both produce and respond in a growth-stimulatory manner to TGFβ. With TGFβ, which is a growth inhibitor for certain epithelial and other cell types, the loss of the normal inhibitory response in transformed cells could have the same result as the activation of a growth-stimulatory response.

Two proto-oncogenes, erbB and fms, encode growth factor receptors. In the erbB case, the viral erbB aberrant receptor produced is truncated and appears to be constitutively activated without the need for a growth factor. Recent studies suggest that the p21 product of the ras oncogene may be an obligatory intermediate in transducing the growth factor signal. Activation of ras may, therefore, activate the growth factor pathway without the need for either a growth factor or its receptor. The transcription of myc and fos is induced by growth factor stimulation of quiescent cells. The protein products of both are nuclear associated and conceivably could be involved in regulating other genes important in the control of cell proliferation. Activation or inappropriate expression of either myc or fos could produce the same end result as stimulation of a growth factor pathway leading to a growth advantage.

Study of the molecular mechanism(s) of growth factor action has just begun. The excitement and attention focused on cellular oncogenes in recent years is now turning toward growth factors, not only as they concern the control of normal cell growth but also the involvement of growth factor-initiated pathways in the etiology of cancer.

One important implication of the molecular dissection of growth control is the identification of specific genes important in growth regulation. The genes encoding growth factors, growth factor receptors, and the post-receptor machinery (i.e., the products of the sis, erbB, fms, ras, fos, myb, and myc proto-oncogenes as well as the p53 gene) may be a significant subset of these pivotal regulatory genes. The cell specificity of these genes (see Table 1) may imply that it would be possible to treat neoplastic diseases with a more targeted arsenal of therapeutic agents which focus their effects on a narrower range of proliferative cells than today's drugs with more generalized actions. In this way, an agent which might interfere with the TGFβ-sis-PDGF pathway might inhibit mainly mesenchymal cell proliferation in a sarcoma, leaving untouched the proliferation of normal cells in the hemopoietic lineage and the intestinal epithelium, so often a side effect of the current generation of chemotherapeutic agents.