Wang Shan-Shan, Gu Yi-Feng, Wolff Nicholas, Stefanius Karoliina, Christie Alana, Dey Anwesha, Hammer Robert E, Xie Xian-Jin, Rakheja Dinesh, Pedrosa Ivan, Carroll Thomas, McKay Renée M, Kapur Payal, Brugarolas James
Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16538-43. doi: 10.1073/pnas.1414789111. Epub 2014 Oct 30.
Why different species are predisposed to different tumor spectra is not well understood. In particular, whether the physical location of tumor suppressor genes relative to one another influences tumor predisposition is unknown. Renal cancer presents a unique opportunity to explore this question. Renal cell carcinoma (RCC) of clear-cell type (ccRCC), the most common type, begins with an intragenic mutation in the von Hippel-Lindau (VHL) gene and loss of 3p (where VHL is located). Chromosome 3p harbors several additional tumor suppressor genes, including BRCA1-associated protein-1 (BAP1). In the mouse, Vhl is on a different chromosome than Bap1. Thus, whereas loss of 3p in humans simultaneously deletes one copy of BAP1, loss of heterozygosity in the corresponding Vhl region in the mouse would not affect Bap1. To test the role of BAP1 in ccRCC development, we generated mice deficient for either Vhl or Vhl together with one allele of Bap1 in nephron progenitor cells. Six2-Cre;Vhl(F/F);Bap1(F/+) mice developed ccRCC, but Six2-Cre;Vhl(F/F) mice did not. Kidneys from Six2-Cre;Vhl(F/F);Bap1(F/+) mice resembled kidneys from humans with VHL syndrome, containing multiple lesions spanning from benign cysts to cystic and solid RCC. Although the tumors were small, they showed nuclear atypia and exhibited features of human ccRCC. These results provide an explanation for why VHL heterozygous humans, but not mice, develop ccRCC. They also explain why a mouse model of ccRCC has been lacking. More broadly, our data suggest that differences in tumor predisposition across species may be explained, at least in part, by differences in the location of two-hit tumor suppressor genes across the genome.
为何不同物种易患不同类型的肿瘤，目前尚未完全明确。特别是，肿瘤抑制基因彼此之间的物理位置是否会影响肿瘤易感性尚不清楚。肾癌为探索这一问题提供了独特的契机。透明细胞型肾细胞癌（ccRCC）是最常见的肾癌类型，其始于von Hippel-Lindau（VHL）基因的基因内突变以及3p（VHL所在位置）的缺失。3号染色体还包含其他几个肿瘤抑制基因，包括BRCA1相关蛋白-1（BAP1）。在小鼠中，Vhl位于与Bap1不同的染色体上。因此，人类3p缺失会同时删除一个BAP1拷贝，而小鼠相应Vhl区域的杂合性缺失不会影响Bap1。为了测试BAP1在ccRCC发生发展中的作用，我们在肾祖细胞中生成了Vhl或Vhl与一个Bap1等位基因均缺失的小鼠。Six2-Cre;Vhl(F/F);Bap1(F/+)小鼠发生了ccRCC，但Six2-Cre;Vhl(F/F)小鼠未发生。Six2-Cre;Vhl(F/F);Bap1(F/+)小鼠的肾脏与患有VHL综合征的人类肾脏相似，包含从良性囊肿到囊性和实性RCC的多个病变。尽管肿瘤较小，但它们显示出核异型性，并表现出人类ccRCC的特征。这些结果解释了为什么VHL杂合的人类会发生ccRCC，而小鼠不会。它们还解释了为什么一直缺乏ccRCC的小鼠模型。更广泛地说，我们的数据表明，不同物种间肿瘤易感性的差异可能至少部分是由全基因组中双打击肿瘤抑制基因位置的差异所解释的。
