Metastatic behavior of the RIF-1 murine fibrosarcoma: inhibited by hypophysectomy and partially restored by growth hormone replacement.

Abstract

We recently demonstrated that hypophysectomy profoundly inhibits metastatic behavior in the MGH-OGS murine osteosarcoma model and speculated that this effect is related at least in part to ablation of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. In this study, we determined whether the administration of GH to animals rendered GH and IGF-I deficient by hypophysectomy attenuates the inhibitory effects of hypophysectomy on metastatic behavior. Metastatic behavior was assayed by counting visible metastases in lungs 3 weeks after tail vein injection of RIF-I fibrosarcoma cells to control mice (n = 29), hypophysectomized mice (n = 19), and hypophysectomized mice administered 0.05 microgram/g body weight recombinant human GH twice daily (n = 21). Twenty of 21 hypophysectomized mice receiving GH, eight of 19 hypophysectomized mice not receiving GH, and 26 of 29 controls had grossly visible pulmonary metastases 3 weeks after intravenous injection of 5 x 10(5) cells; mean numbers +/- SD of gross metastases were 38.4 +/- 11.3, 6.4 +/- 2.2, and 13.1 +/- 2.8 in the three groups, respectively. The presence (P < .005, chi-square test) and number (P = .0003, Mann-Whitney U test) of metastases were significantly reduced in hypophysectomized hosts compared with control hosts and were significantly higher in hypophysectomized, GH-replaced hosts compared with hypophysectomized hosts (P < .001, chi-square test; P = .011, Mann-Whitney U test), while the difference in presence and extent of metastases between control and hypophysectomized, GH-replaced hosts was not statistically significant. These data support the hypothesis that the status of the host with respect to GH and/or GH-dependent factors such as IGF-I influences the metastatic behavior of certain neoplasms. Our results raise the possibility that compounds that reduce GH output or interfere with GH action, such as somatostatin analogues, GH antagonists, IGF antagonists, and GH-releasing hormone antagonists, may suppress metastatic behavior of certain neoplasms.