A hypothesis is presented that states that tumor viruses produce their transforming action on cells, at least in part, by the production of endogenous polypeptide growth-stimulatory factors. Cells transformed by murine sarcoma viruses have been found to have reduced or absent cell surface receptors for epidermal growth factor (EGF), as compared to the untransformed parental cells and to cells transformed by other viruses. Sarcoma virus-transformed cells are shown to release a family of polypeptide growth factors into the supernatant fluids in cell cultures. These factors, with molecular weights of approximately 25,000, 12,000, and 7,000, stimulate cell division and compete for EGF receptors. The new sarcoma growth factors are not produced by untransformed cells or by DNA virus-transformed cells. Sarcoma growth factors induce normal fibroblasts to grow in soft agar and to express some of the phenotypic properties of transformed cells; these effects are dependent on the continued presence of the factor.

A human fibrosarcoma was found that had normal levels of EGF receptors, but no apparent multiplication-stimulating activity (MSA) receptors. Since normal fibroblasts have MSA receptors, it was decided to test whether the receptor-negative cell was producing a related growth factor. In this case a family of related growth polypeptides was found that interacted with MSA receptors, but not with EGF receptors, and stimulated cell division in cells of various species. The activities of both the sarcoma growth factors and the MSA-related human fibrosarcoma growth factors are heat stable, protease sensitive, and sensitive to disulfide reducing agents. The endogenous production of polypeptide growth factors by cells that are able to respond to their own products may represent a general mechanism for cell transformation.

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Presented at the John E. Fogarty International Center Conference on Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md.

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