Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy.

BACKGROUND We recently reported that human osteogenic sarcoma cells are mitogenically responsive in tissue culture to insulin-like growth factor I (IGF-I), a mitogen important in the regulation of cellular proliferation of many tissues, including bone. PURPOSE The present study was designed to determine whether these in vitro observations could be extended to an in vivo experimental system and whether reduction of IGF-I levels by hypophysectomy could inhibit the aggressive metastatic behavior of osteosarcoma. METHODS We used standard competitive binding and affinity-labeling techniques to characterize the IGF-I-binding sites of MGH-OGS, a model of human osteosarcoma. Radioimmunoassay of serum, preprocessed to remove IGF-binding proteins, was used to quantitate IGF-I levels. In vitro proliferative response of MGH-OGS cells to IGF-I and other pituitary-dependent factors was determined by thymidine-incorporation experiments. In vivo growth of the neoplasm in 12 hypophysectomized C3H mice and in 14 control C3H mice was determined by serial measurements of implanted tumors and by gross and microscopic examination of the lungs for metastases. RESULTS MGH-OGS exhibited specific binding sites for 1.39 pmol IGF-I per milligram MGH-OGS cellular membrane protein, a concentration similar to that which we previously reported for human osteosarcoma. In tissue culture, MGH-OGS exhibited mitogenic response to IGF-I (P less than .01) but not to other pituitary-dependent factors. Hypophysectomy reduced levels of circulating IGF-I to 15% of control, significantly inhibited local growth of MGH-OGS tumors (increased time for growth to 1 cm3 from 49 to 84 days, P less than .001), and profoundly inhibited metastatic behavior (decrease in mean number of metastases per host from 16 to less than one; P less than .001). CONCLUSIONS This study is the first to document the profound inhibitory effect of hypophysectomy on the metastatic behavior of an experimental sarcoma. We conclude that the metastatic behavior exhibited by MGH-OGS osteosarcoma is dependent on pituitary factors, and we suggest that the inhibitory effects of hypophysectomy are related, at least in part, to the reduction of IGF-I levels.