Momoi Yusaku, Nishida Jun, Miyakuni Kosuke, Kuroda Masafumi, Kubota Shimpei I, Miyazono Kohei, Ehata Shogo
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan.
International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Bunkyo-ku, Japan.
Cancer Sci. 2021 Aug;112(8):3136-3149. doi: 10.1111/cas.15007. Epub 2021 Jun 28.
Intratumoral heterogeneity, including in clear cell renal cell carcinoma, is a potential cause of drug resistance and metastatic cancer progression. We specified the heterogeneous population marked by endoglin (also known as CD105) in a preclinical model of clear cell renal cell carcinoma progression. Highly malignant derivatives of human clear cell renal cell carcinoma OS-RC-2 cells were established as OS5Ks by serial orthotopic inoculation in our previous study. Expression of both ENG (encoding endoglin) mRNA and protein were heterogeneously upregulated in OS5Ks, and the endoglin-positive (ENG ) population exhibited growth dependency on endoglin in anchorage-independent cultures. Despite the function of endoglin as a type III receptor, transforming growth factor β and bone morphogenetic protein-9 signaling were unlikely to contribute to the proliferative phenotype. Although endoglin has been proposed as a marker for renal cancer-initiating cells, the OS5K-3 ENG population did not enrich other reported cancer-initiating cell markers or differentiate into the ENG population. Mouse tumor inoculation models revealed that the tumor-forming capabilities of OS5K-3 ENG and ENG cells in vivo were highly dependent on the microenvironment, with the renal microenvironment most preferable to ENG cells. In conclusion, the renal microenvironment, rather than the hypothesized ENG cell-centered hierarchy, maintains cellular heterogeneity in clear cell renal cell carcinoma. Therefore, the effect of the microenvironment should be considered when evaluating the proliferative capability of renal cancer cells in the experimental settings.
肿瘤内异质性，包括在透明细胞肾细胞癌中，是耐药性和转移性癌症进展的一个潜在原因。我们在透明细胞肾细胞癌进展的临床前模型中明确了以内皮糖蛋白（也称为CD105）为特征的异质性群体。在我们之前的研究中，通过连续原位接种将人透明细胞肾细胞癌OS-RC-2细胞的高恶性衍生物建立为OS5K细胞系。ENG（编码内皮糖蛋白）mRNA和蛋白的表达在OS5K细胞系中均呈异质性上调，并且内皮糖蛋白阳性（ENG⁺）群体在非锚定依赖培养中表现出对内皮糖蛋白的生长依赖性。尽管内皮糖蛋白作为III型受体发挥作用，但转化生长因子β和骨形态发生蛋白-9信号通路不太可能促成增殖表型。尽管内皮糖蛋白已被提议作为肾癌起始细胞的标志物，但OS5K-3 ENG⁺群体并未富集其他报道的癌症起始细胞标志物，也未分化为ENG⁻群体。小鼠肿瘤接种模型显示，OS5K-3 ENG⁺和ENG⁻细胞在体内的成瘤能力高度依赖于微环境，其中肾脏微环境对ENG⁺细胞最为有利。总之，肾脏微环境而非假设的以ENG⁺细胞为中心的层次结构维持了透明细胞肾细胞癌中的细胞异质性。因此，在实验环境中评估肾癌细胞的增殖能力时应考虑微环境的影响。
