Thompson Henry J, McGinley John N, Spoelstra Nicole S, Jiang Weiqin, Zhu Zongjian, Wolfe Pamela
Cancer Prevention Laboratory, Colorado State University, Fort Collins, Colorado 80523, USA.
Cancer Res. 2004 Aug 15;64(16):5643-50. doi: 10.1158/0008-5472.CAN-04-0787.
Inhibition of mammary carcinogenesis by dietary energy restriction is associated with a decrease in cell proliferation and the induction of apoptosis. Although changes in the metabolism of insulin-like growth factor I and glucocorticoids have been proposed to modulate these cellular processes, limitations in blood supply could induce similar effects. To investigate this possibility, female Sprague Dawley rats were given an injection of 1-methyl-1-nitrosourea and fed purified diets ad libitum or at 60% ad libitum intake, i.e., 40% dietary energy restriction. Premalignant mammary pathologies and mammary adenocarcinomas obtained from these rats were processed for vascular density analysis via CD-31 immunostaining. Vascular density, measured as vessels/unit area, of premalignant mammary pathologies and adenocarcinomas from dietary energy restriction rats was reduced 31 and 39%, respectively (P < 0.01). This effect, which was observed in a 50-microm wide band of tissue surrounding each pathology, was exerted on blood vessels > 25 microm2. Conversely, intratumoral vascular density was unaffected by dietary energy restriction. cDNA microarray and Western blot analyses of adenocarcinomas for evidence of dietary energy restriction-mediated effects on vascularization revealed that only the level of vascular endothelial growth factor receptor protein Flk-1 was significantly reduced (P < 0.001). It appears that dietary energy restriction imposes limitations in the supply of blood to developing pathologies, an effect that could directly inhibit the carcinogenic process. The vascular density data imply that dietary energy restriction inhibited the growth of endothelial cells but leave unresolved the question of whether dietary energy restriction had a specific effect on angiogenesis. The factors that account for the failure of dietary energy restriction to limit intratumoral vascularization are not obvious and merit additional investigation.
饮食能量限制对乳腺癌发生的抑制作用与细胞增殖的减少及细胞凋亡的诱导有关。尽管有人提出胰岛素样生长因子I和糖皮质激素代谢的变化可调节这些细胞过程，但血液供应受限也可能产生类似效果。为研究这种可能性，给雌性斯普拉格-道利大鼠注射1-甲基-1-亚硝基脲，并随意喂食纯化日粮或按随意摄入量的60%喂食，即饮食能量限制40%。对从这些大鼠获得的癌前乳腺病变和乳腺腺癌进行处理，通过CD-31免疫染色进行血管密度分析。饮食能量限制大鼠的癌前乳腺病变和腺癌的血管密度（以每单位面积的血管数衡量）分别降低了31%和39%（P<0.01）。这种效应在每个病变周围50微米宽的组织带中观察到，作用于直径>25微米2的血管。相反，肿瘤内血管密度不受饮食能量限制的影响。对腺癌进行cDNA微阵列和蛋白质印迹分析，以寻找饮食能量限制介导的血管生成效应的证据，结果显示只有血管内皮生长因子受体蛋白Flk-1的水平显著降低（P<0.001）。看来饮食能量限制对正在发展的病变的血液供应施加了限制，这种效应可能直接抑制致癌过程。血管密度数据表明饮食能量限制抑制了内皮细胞的生长，但饮食能量限制是否对血管生成有特定作用这一问题仍未解决。饮食能量限制未能限制肿瘤内血管生成的原因尚不明确，值得进一步研究。
