Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1.
Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1.
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DOI：
10.1186/1471-2490-8-7
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发表时间：
2008-04-23
期刊：
影响因子：
2
通讯作者：
Reeder JE
中科院分区：
文献类型：
--
作者：
Johnson AM;O'Connell MJ;Miyamoto H;Huang J;Yao JL;Messing EM;Reeder JE
类固醇激素影响有丝分裂信号通路、细胞凋亡和细胞周期检查点，人们早就知道男性膀胱癌 (BC) 的发病率是女性的几倍，这种差异不能仅归因于环境或生活方式因素。阉割可降低啮齿类动物化学诱发 BC 的发生率。目前尚不清楚这种效应是由于激素对致癌物激活/失活的影响，还是对尿路上皮细胞增殖或其他恶性过程的直接影响。我们研究了去势对 UPII-SV40T 转基因小鼠 BC 生长的影响，该小鼠在尿路上皮特异性表达 SV40 T 抗原并可靠地发展 BC。此外，由于 UPII-SV40T 小鼠中的 BC 生长是外生的，因此我们推测 BC 生长依赖于血管生成，而血管生成反过来又对雄激素有反应。使用基于平板探测器的锥形束计算机断层扫描 (FPDCT) 纵向测量假手术、去势或去势并补充二氢睾酮 (DHT) 的 UPII-SV40T 雄性小鼠的外生性 BC 生长。定量检测人类正常膀胱和 BC 活检组织以及小鼠膀胱的血小板反应蛋白-1 (TSP1) 蛋白表达。与完整小鼠 (p = 0.0071) 和给予 DHT 的阉割小鼠 (p = 0.0233; 单向方差分析，JMP 6.0.3，SAS Institute, Inc.) 相比，24 周龄阉割的小鼠在 32 周时 BC 体积减少。无论雄激素受体表达水平如何，膀胱癌细胞系对 DHT 治疗的反应是增殖增加。 TSP1 是一种抗血管生成因子，其表达受到雄激素的抑制，与野生型相比，UPII-SV40T 小鼠膀胱中的表达降低。与完整小鼠相比，去势增加了 UPII-SV40T 小鼠的 TSP1 水平。在同一患者的正常组织和恶性组织的 10 例膀胱活检中，有 8 例的 TSP1 蛋白表达较高。 FPDCT 允许纵向监测 BC UPII-SV40T 模型中的外生肿瘤生长，从而绕过对化学致癌剂的需求，这会混淆雄激素效应的分析。雄激素在体外和体内增加肿瘤细胞的生长并降低 TSP1 的表达，这可能解释了去势的治疗作用。这种效应可能部分解释了 BC 发病率的性别差异，并暗示抗雄激素疗法可能有效预防和治疗 BC。
Steroid hormones influence mitogenic signaling pathways, apoptosis, and cell cycle checkpoints, and it has long been known that incidence of bladder cancer (BC) in men is several times greater than in women, a difference that cannot be attributed to environmental or lifestyle factors alone. Castration reduces incidence of chemically-induced BC in rodents. It is unclear if this effect is due to hormonal influences on activation/deactivation of carcinogens or a direct effect on urothelial cell proliferation or other malignant processes. We examined the effect of castration on BC growth in UPII-SV40T transgenic mice, which express SV40 T antigen specifically in urothelium and reliably develop BC. Furthermore, because BC growth in UPII-SV40T mice is exophytic, we speculated BC growth was dependent on angiogenesis and angiogenesis was, in turn, androgen responsive. Flat panel detector-based cone beam computed tomography (FPDCT) was used to longitudinally measure exophytic BC growth in UPII-SV40T male mice sham-operated, castrated, or castrated and supplemented with dihydrotestosterone (DHT). Human normal bladder and BC biopsies and mouse bladder were examined quantitatively for thrombospondin-1 (TSP1) protein expression. Mice castrated at 24 weeks of age had decreased BC volumes at 32 weeks compared to intact mice (p = 0.0071) and castrated mice administered DHT (p = 0.0233; one-way ANOVA, JMP 6.0.3, SAS Institute, Inc.). Bladder cancer cell lines responded to DHT treatment with increased proliferation, regardless of androgen receptor expression levels. TSP1, an anti-angiogenic factor whose expression is inhibited by androgens, had decreased expression in bladders of UPII-SV40T mice compared to wild-type. Castration increased TSP1 levels in UPII-SV40T mice compared to intact mice. TSP1 protein expression was higher in 8 of 10 human bladder biopsies of normal versus malignant tissue from the same patients. FPDCT allows longitudinal monitoring of exophytic tumor growth in the UPII-SV40T model of BC that bypasses need for chemical carcinogens, which confound analysis of androgen effects. Androgens increase tumor cell growth in vitro and in vivo and decrease TSP1 expression, possibly explaining the therapeutic effect of castration. This effect may, in part, explain gender differences in BC incidence and implies anti-androgenic therapies may be effective in preventing and treating BC.