11246 Health Sciences East Tower, University of California, San Francisco, CA 94143-0521, USA.
FASEB J. 2014 Mar;28(3):1446-53. doi: 10.1096/fj.13-245621. Epub 2013 Dec 12.
Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1(+/+) MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm(3) (SE, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm(3), 12 mice) were greatly reduced in AQP1(-/-) MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1(-/-) MMTV-PyVT mice, with reduced vessel density. HIF-1α expression was increased in tumors in AQP1(-/-) MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1(+/+) MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.
水通道蛋白 1（AQP1）是一种强烈表达于肿瘤微血管内皮细胞的质膜水转运蛋白。我们之前报道过 AQP1 缺陷小鼠植入肿瘤中的血管生成受损，以及 AQP1 缺陷内皮细胞在体外迁移减少。在这里，我们研究了在自发性形成高分化、腔型乳腺腺瘤伴肺转移的小鼠中 AQP1 缺失的后果[鼠乳腺肿瘤病毒驱动的多瘤病毒中 T 抗原（MMTV-PyVT）]。AQP1(+/+) MMTV-PyVT 小鼠在 98 天龄时发展为大的乳腺肿瘤，总肿瘤质量为 3.5±0.5g，体积为 265±36mm(3)(SE，11 只小鼠)。AQP1(-/-) MMTV-PyVT 小鼠的肿瘤质量（1.6±0.2g）和体积（131±15mm(3)，12 只小鼠）显著降低（P<0.005）。AQP1(-/-) MMTV-PyVT 小鼠肿瘤中的 CD31 免疫荧光显示微血管解剖异常，血管密度降低。AQP1(-/-) MMTV-PyVT 小鼠肿瘤中 HIF-1α 的表达增加。肺转移的数量（5±1/只小鼠）远低于 AQP1(+/+) MMTV-PyVT 小鼠（31±8/只小鼠，P<0.005）。这些结果表明 AQP1 是肿瘤血管生成的重要决定因素，因此可能是实体瘤辅助治疗的潜在药物靶点。
