Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Cancer Prev Res (Phila). 2011 Sep;4(9):1426-35. doi: 10.1158/1940-6207.CAPR-11-0219. Epub 2011 Jun 16.
Helicobacter pylori infection promotes male predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies showed that prophylactic 17β-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and tamoxifen (TAM) on H. pylori-induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks postinfection (WPI), mice were implanted with E2, TAM, both E2 and TAM, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression, and immune cell infiltration were evaluated and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori-infected males receiving E2 and/or TAM, whereas 40% of infected untreated males developed gastric cancer. E2, TAM, and their combination significantly reduced gastric precancerous lesions in infected males compared with infected untreated males (P < 0.001, 0.01, and 0.01, respectively). However, TAM did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or TAM (n = 363 and n = 144, Q < 0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or TAM deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared with controls, E2 decreased gastric mRNA (Q < 0.05) and serum levels (P < 0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P < 0.01). Prevention of H. pylori-induced gastric cancer by E2 and TAM may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts, and downregulation of oncogenic pathways.
幽门螺杆菌感染促进人类男性为主的胃腺癌。雌激素降低胃癌风险，先前的研究表明，预防性 17β-雌二醇（E2）在 INS-GAS 小鼠中可降低幽门螺杆菌引起的癌变。我们研究了 E2 和他莫昔芬（TAM）对雄性和雌性 INS-GAS 小鼠幽门螺杆菌诱导的胃癌的影响。在感染后 16 周（WPI）确认了强有力的胃病理学后，将 E2、TAM、E2 和 TAM 两者或安慰剂丸植入小鼠体内 12 周。在 28 WPI 时，评估胃组织病理学、基因表达和免疫细胞浸润，并测量血清炎症细胞因子。治疗后，接受 E2 和/或 TAM 的感染雄性中未观察到胃癌，而未接受治疗的感染雄性中有 40%发展为胃癌。E2、TAM 及其组合与未接受治疗的感染雄性相比，显著减少了感染雄性的胃癌前病变（P < 0.001、0.01 和 0.01）。然而，无论感染状态如何，TAM 均未改变雌性的病理。接受 E2 或 TAM 治疗的雄性（n = 363 和 n = 144，Q < 0.05）差异表达的基因与癌症和细胞运动高度相关，表明在减少胃病变方面存在重叠途径。E2 或 TAM 失调的基因与转移（PLAUR 和 MMP10）和 Wnt 抑制（FZD6 和 SFRP2）相关。与对照组相比，E2 降低了胃 mRNA（Q < 0.05）和血清水平（P < 0.05）的 CXCL1，一种中性粒细胞趋化因子，导致中性粒细胞浸润减少（P < 0.01）。E2 和 TAM 预防幽门螺杆菌诱导的胃癌可能通过雌激素信号介导，与 CXCL1 减少、中性粒细胞计数减少和致癌途径下调有关。
