Howe S R, Pass H I, Ethier S P, Matthews W J, Walker C
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville 78957, USA.
Cancer Res. 1996 Sep 1;56(17):4049-55.
Uterine leiomyoma is an estrogen-responsive tumor, and the present studies examine the ability of the antiestrogen tamoxifen to modulate leiomyoma cell growth. Tamoxifen is an effective form of hormonal therapy for breast cancer, although the mechanism by which tamoxifen inhibits tumor growth is not well understood and may involve mechanisms other than the action of tamoxifen as an estrogen antagonist. Tamoxifen was found to inhibit the proliferation of three of five leiomyoma-derived cell lines (ELT cell lines) in vitro, including an estrogen receptor-negative cell line. The ability of tamoxifen to decrease leiomyoma growth was found to correlate with expression of insulin-like growth factor I (IGF-I) by the tumor cells, suggesting that the inhibitory effects of tamoxifen were associated with expression of this growth factor. The existence of an IGF-I autocrine loop in the cells was investigated, because transcripts for both IGF-I and its cognate receptor were expressed in the tamoxifen-responsive cell lines. An IGF-I RIA demonstrated secreted IGF-I protein in serum-free medium conditioned by the IGF-I-expressing cell line ELT 3, and this same medium supported the growth of IGF-requiring MCF-10A cells, indicating the presence of biologically active IGF-I in the conditioned medium. Exogenous IGF-I stimulated ELT 3 cell proliferation, confirming that this growth factor is mitogenic for leiomyoma cells. IGF-I neutralizing antibody inhibited ELT 3 growth, indicating that the levels of IGF-I produced by the leiomyoma cells were physiologically significant. These data demonstrate the existence of an IGF-I autocrine loop in tamoxifen-sensitive leiomyoma cells, supporting the hypothesis that the presence of an IGF-I autocrine loop predicts uterine fibroid responsiveness to tamoxifen.
子宫平滑肌瘤是一种雌激素反应性肿瘤，目前的研究考察了抗雌激素他莫昔芬调节平滑肌瘤细胞生长的能力。他莫昔芬是乳腺癌激素治疗的一种有效形式，尽管他莫昔芬抑制肿瘤生长的机制尚未完全明了，可能涉及除他莫昔芬作为雌激素拮抗剂作用之外的其他机制。研究发现他莫昔芬在体外可抑制5种源自平滑肌瘤的细胞系（ELT细胞系）中的3种的增殖，包括一种雌激素受体阴性细胞系。发现他莫昔芬降低平滑肌瘤生长的能力与肿瘤细胞中胰岛素样生长因子I（IGF-I）的表达相关，提示他莫昔芬的抑制作用与该生长因子的表达有关。对细胞中IGF-I自分泌环的存在进行了研究，因为IGF-I及其同源受体的转录本在对他莫昔芬有反应的细胞系中均有表达。一项IGF-I放射免疫分析显示，由表达IGF-I的细胞系ELT 3在无血清培养基中分泌的IGF-I蛋白，并且同样的培养基支持需要IGF的MCF-10A细胞生长，表明在条件培养基中存在生物活性IGF-I。外源性IGF-I刺激ELT 3细胞增殖，证实该生长因子对平滑肌瘤细胞有促有丝分裂作用。IGF-I中和抗体抑制ELT 3生长，表明平滑肌瘤细胞产生的IGF-I水平具有生理意义。这些数据证明在对他莫昔芬敏感的平滑肌瘤细胞中存在IGF-I自分泌环，支持了IGF-I自分泌环的存在可预测子宫肌瘤对他莫昔芬反应性的假说。
