TRANSFORMING GROWTH-FACTORS IN SOLID HUMAN-MALIGNANT NEOPLASMS

Abstract

Surgically removed solid human benign and malignant neoplasms and nonneoplastic tissues were examined for the presence of transforming growth factors (TGF). TGF 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. Acid-ethanol 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 caused 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 MW 3000-25,000 range with the apparent MW varying depending on the type of tumor being studied and the indicator cells used. At least 3 TGF are present in human tumors. Evidence is presented differentiating these TGF 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 6000) and large (12,000-20,000) apparent MW, 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 TGF 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.