Fibrosis without an Antitumor Effect in Nude Mice 1 Induces Cachexia and Systemic β Transforming Growth Factor

While stimulating the growth of fibroblasts, transforming growth factor ,) I ( U.I ,n ) inhibits the growth of various normal and malignant cell lines in vitro. We studied the effects of TGF-/31 in vivo. The level of TGF-01 in serum was maximally elevated 2 h after injecting 1 fid of I25I-TGF-/31into the peritoneal cavity of nude mice. Five h after the ¡.p. administration of 10 ng of unlabeled TGF-/31, 20 ng/ml of TGF-/J-like material in serum were detected by a radioreceptor assay on A549 lung carcinoma cells. Trichloroacetic acid-precipitable '"I-TGF-/31 was taken up by liver, spleen, lungs, kidneys, and tumor tissue but not by the brain. At doses exceeding 2 jig/day, TGF-,01 induced a generalized interstitial fibrosis and a cachexia, which was not mediated by elevated serum levels of tumor necrosis factor a as determined by Western blot analysis and enzyme-linked immunosorbent assay. A total of 200,000 cells of the estrogen receptor-negative human breast cancer line MDA-MB-231, which had been shown to be maximally growth inhibited in vitro by 40 pM TGF-/31 and to have high-affinity receptors (9, 11, 12), were injected into the mammary fat pad of each nude mouse. The duration of treatment was 16 days with ten animals in the control group and five animals in the treated groups. The dose ranged from 1 to 4 ^g per animal daily. The treatment was started 24 h after the injection of the tumor cells. Tumor growth was not significantly affected at either nontoxic or toxic doses of TGF-/91. Thus, we have demonstrated that TGF-/31, apart from being a local growth factor, has systemic effects, such as cachexia and multiple fibrosis. Its role as an antitumor agent may be limited.