Heterogenous expression of endoglin marks advanced renal cancer with distinct tumor microenvironment fitness.
Heterogenous expression of endoglin marks advanced renal cancer with distinct tumor microenvironment fitness.
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DOI：
10.1111/cas.15007
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发表时间：
2021-08
期刊：
影响因子：
5.7
通讯作者：
Ehata S
中科院分区：
文献类型：
--
作者：
Momoi Y;Nishida J;Miyakuni K;Kuroda M;Kubota SI;Miyazono K;Ehata S
肿瘤内异质性，包括透明细胞肾细胞癌，是耐药和转移性癌症进展的潜在原因。我们在透明细胞肾细胞癌进展的临床前模型中指定了内啡肽（也称为CD105）标记的异质群体。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的高度恶性衍生物OS‐RC‐2细胞建立为OS5Ks。在OS5Ks中，ENG（编码内啡肽）mRNA和蛋白的表达均异质性上调，内啡肽阳性（ENG+）群体在锚定独立培养中表现出对内啡肽的生长依赖。尽管内啡肽作为III型受体具有功能，但转化生长因子β和骨形态发生蛋白- 9信号传导不太可能促进增生性表型。虽然内皮素已被认为是肾癌起始细胞的标记物，但OS5K‐3 ENG+群体并没有丰富其他已报道的癌症起始细胞标记物，也没有分化为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，其中肾微环境对ENG+细胞最有利。总之，肾微环境，而不是假设的ENG+细胞中心层次，维持透明细胞肾细胞癌的细胞异质性。因此，在实验环境下评价肾癌细胞的增殖能力时，应考虑微环境的影响。研究了内啡肽表达在肾肿瘤发生和转移中的作用。我们建立了一个原位肿瘤模型，以确定肾癌细胞中内啡肽标记的异质群体。结果表明，肾脏微环境，而不是假设的内啡肽阳性细胞中心层次，维持了肾癌的细胞异质性。
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. The impact of endoglin expression in renal tumorigenesis and metastasis was examined. We developed an orthotopic tumor model to identify the heterogeneous population marked by endoglin in renal cancer cells. The results showed that the renal microenvironment, rather than the hypothesized endoglin‐positive cell‐centered hierarchy, maintains cellular heterogeneity in renal cancer.
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影响因子：
--
作者：
Takahashi K;Kubota SI;Ehata S;Ueda HR;Miyazono K
通讯作者：
Miyazono K
影响因子：
4.8
作者：
Bussolati, Benedetta;Bruno, Stefania;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
肾癌干细胞的生物标志物发现。
DOI：
10.1002/cjp2.91
发表时间：
2018-01
期刊：
The journal of pathology. Clinical research
影响因子：
--
作者：
Corrò C;Moch H
通讯作者：
Moch H
影响因子：
8.8
作者：
Saroufim, A.;Messai, Y.;Hasmim, M.;Rioux, N.;Iacovelli, R.;Verhoest, G.;Bensalah, K.;Patard, J-J;Albiges, L.;Azzarone, B.;Escudier, B.;Chouaib, S.
通讯作者：
Chouaib, S.
影响因子：
3.7
作者：
Khan MI;Czarnecka AM;Lewicki S;Helbrecht I;Brodaczewska K;Koch I;Zdanowski R;Król M;Szczylik C
通讯作者：
Szczylik C