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Transforming Growth Factors in Solid Human Malignant Neoplasms¹

Departments of Cell Biology [K. A. N., J. H., H. L. M.] and Pathology [J. H., H. L. M.], Section of Experimental Pathology, Mayo Clinic, Foundation and Medical School, Rochester, Minnesota 55905

Surgically removed solid human benign and malignant neoplasms and nonneoplastic tissues were examined for the presence of transforming growth factors (TGFs). TGFs are polypeptide growth factor-like substances which cause the appearance of a reversible neoplastic phenotype in nontransformed, anchorage-dependent cells in culture, including the induction of the ability to grow while suspended in semisolid medium. Acidethanol extracts from adenocarcinomas of the breast, colon, kidney, and ovary; fibrosarcoma and leiomyosarcoma; Hodgkin's lymphoma; fibroadenoma of the breast; uterine leiomyoma; and nonneoplastic kidney and lung were found to cause growth in soft agar of both nontransformed mouse AKR-2B and rat NRK cells. This colony-stimulating activity, where tested, was heat and acid stable but was destroyed by trypsin and dithiothreitol treatment, indicating that the activity is due to a polypeptide with disulfide bonds. Extracts from several of the tumors provided sufficient material for purification by molecular sieve chromatography. Peaks of colony-stimulating activity from a Bio-Gel P-60 column eluted with 1 M acetic acid were detected in the M_r 3,000 to 25,000 range with the apparent molecular weight varying depending on the type of tumor being studied and the indicator cells used. The data suggest that at least three TGFs are present in human tumors. Evidence is presented differentiating these TGFs into TGFa, which has selective activity for stimulating AKR-2B cells, and TGFn, which has selective activity for stimulating NRK cells. The TGFn activity was further subdivided into a TGFns fraction and TGFnl fraction, denoting small (less than 6,000) and large (12,000 to 20,000) apparent molecular weights, respectively. The TGFa and TGFnl activities were present in malignant and nonneoplastic (kidney and lung) tissue, whereas the TGFns activity predominated in benign neoplasms. These TGFs exhibited no competition with epidermal growth factor for binding to the epidermal growth factor receptor, and the TGFnl activity was potentiated by epidermal growth factor.

¹ Supported by USPHS Grant CA 27217 awarded by the National Cancer Institute, Department of Health and Human Services. Presented in part at the American Society for Cell Biology meeting in Anaheim, Calif. November 1981 (10).

² Recipient of NIH Training Grant AM 07147.

³ To whom requests for reprints should be addressed.

Received 8/16/82. Accepted 1/21/83.