Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
J Urol. 2012 Aug;188(2):624-31. doi: 10.1016/j.juro.2012.03.113. Epub 2012 Jun 15.
Hypoxia and acidosis develop in in situ tumors as cellular expansion increases the diffusion distance of substrates and metabolites from blood vessels deep to the basement membrane. Prior studies of breast and cervical cancer revealed that cellular adaptation to microenvironmental hypoxia and acidosis is associated with the transition from in situ to invasive cancer. We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer.
A total of 37 C57BL/6 TRAMP mice were randomized to a control group or to 1 of 4 treatment groups. In the latter groups 200 mM sodium bicarbonate were added to drinking water starting between ages 4 and 10 weeks.
In all 18 controls prostate cancer developed that was visible on 3-dimensional ultrasound at a mean age of 13 weeks. They died within 52 weeks (median 37). When sodium bicarbonate therapy commenced before age 6 weeks in 10 mice, all reached senescence (age 76 weeks) without radiographic evidence of prostate cancer. Histological sections of the prostates in this cohort showed hyperplasia but no cancer in 70% of mice and minimal well differentiated cancer in the remainder. When therapy commenced after age 6 weeks in 9 mice, prostate cancer development was no different from that in controls.
Immunohistochemical staining for carbonic anhydrase 9 in regions of ductal hyperplasia showed increased expression in controls vs the early treatment group. Regional pH perturbation in in situ tumors may be a simple, inexpensive and effective cancer prevention strategy.
随着细胞的扩张增加了基质和代谢物从血管到基底膜深处的扩散距离，原位肿瘤中会出现缺氧和酸中毒。先前对乳腺癌和宫颈癌的研究表明，细胞对微环境缺氧和酸中毒的适应与从原位癌向浸润性癌的转变有关。我们假设，原位肿瘤中酸中毒的减少会改变酸性适应表型的环境选择压力，从而延迟或阻止其向浸润性癌的进化。
共 37 只 C57BL/6 TRAMP 小鼠被随机分为对照组或 4 个治疗组中的 1 个。在后一组中，从 4 到 10 周龄开始，在饮用水中添加 200mM 的碳酸氢钠。
在所有 18 只对照小鼠中，前列腺癌在 3 维超声上可见，平均年龄为 13 周。它们在 52 周内（中位数 37 周）死亡。当 10 只小鼠在 6 周龄之前开始碳酸氢钠治疗时，所有小鼠均达到衰老（76 周龄），没有放射影像学证据表明患有前列腺癌。该队列中前列腺的组织学切片显示，70%的小鼠增生但无癌，其余小鼠有轻微的高分化癌。当 9 只小鼠在 6 周龄后开始治疗时，前列腺癌的发展与对照组无差异。
在导管增生区域用碳酸酐酶 9 的免疫组织化学染色显示，对照组的表达高于早期治疗组。原位肿瘤的区域 pH 波动可能是一种简单、廉价和有效的癌症预防策略。
