We have elucidated the importance of a transforming growth factor (TGF) α and epidermal growth factor receptor autocrine mechanism on the growth of a human ovarian serous cystadenocarcinoma-derived cell line (SHIN-3) in vitro. In this study, we studied the biological significance of this autocrine mechanism in vivo using female athymic nude (nu/nu) mice. We measured the mouse plasma epidermal growth factor and TGFα levels by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Plasma epidermal growth factor concentrations were remarkably decreased by sialoadenectomy (Sx): 410 ± 65 (SE) pg/ml (n = 10) in intact animals; and undetectable in Sx mice (n = 5). Plasma TGFα levels were 90 and 40 pg/ml in intact and in Sx animals, respectively. Ten million SHIN-3 cells inoculated into nu/nu mice formed tumors in 100% of mice, and tumors grew progressively. Implantabilities and tumor growth rates of inoculated cells were not affected by Sx and even by Sx and anti-mouse epidermal growth factor antibody treatment. However, anti-TGFα monoclonal antibody (mAb) administered to SHIN-3 cell-inoculated Sx animals drastically reduced the tumor growth. Although 107 SHIN-3 cells formed tumors in this group, tumor growth was significantly inhibited by 10 µg of anti-TGFα mAb given 3 times a week, and growth inhibitions were more by 20 µg of anti-TGFα mAb. Moreover, as aggressive tumor growth as that in Sx animals was resumed by the cessation of anti-TGFα mAb treatments. All these data suggested the biological importance of a TGFα/epidermal growth factor receptor autocrine mechanism on the growth of this cell line in vivo.

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