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首页> 外文期刊>Pathobiology: journal of immunopathology, molecular and cellular biology >Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27(Kip1): Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity
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Microenvironment-Derived FGF-2 Stimulates Renal Cell Carcinoma Cell Proliferation through Modulation of p27(Kip1): Implications for Spatial Niche Formation and Functional Intratumoral Heterogeneity

机译：微环境衍生的FGF-2通过调节P27（KIP1）刺激肾细胞癌细胞增殖：对空间乳头形成和功能性腹腔内异质性的影响

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Background/Objective: Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of functional intratumoral heterogeneity (ITH). This is highlighted by the finding that tumor cell proliferation and intracellular signaling occur preferentially in the tumor periphery. The driving forces for such a spatial organization are largely unknown. Herein, we investigate the role of the tumor microenvironment in the control of tumor cell proliferation and functional ITH. Methods: Conditioned media (CM) derived from nonmalignant peritumoral kidney tissue were used to stimulate RCC cells in vitro. A neutralization assay was used to characterize the role of FGF-2 in the CM. The molecular mechanisms underlying the action of CM on RCC cells were investigated using immunoblotting, flow cytometry and immunofluorescence microscopy. Lastly, a series of ccRCCs were stained for Ki-67 and p27(Kip1), and expression was analyzed in both tumor periphery and center. Results: We show that CM derived from nonmalignant kidney cells adjacent to an RCC can downregulate the expression of the CDK inhibitor p27(Kip1) through enhanced protein degradation in an FGF-2-dependent fashion. FGF-2 functions mainly through the PI3K/AKT pathway downstream of its receptors, and RCC cells with constitutively high AKT activity show not only an enhanced degradation of p27(Kip1) through the Emi1-Skp2 axis, but also a subcellular mislocalization of p27(Kip1) to the cytoplasmic compartment. Such a mislocalization was also detected in the tumor periphery in vivo suggesting that p27(Kip1) plays an important role in shaping this spatial niche. Conclusions: Our results suggest that the tumor microenvironment is involved in shaping the tumor peripheral niche by stimulating the enhanced proliferation that is characteristic for this zone.
机译：背景/目的：透明细胞肾细胞癌（CCRCC）的特征在于高型功能腹腔内异质性（ITH）。这是通过在肿瘤周边优先发生的肿瘤细胞增殖和细胞内信号传导的发现突出显示。这种空间组织的驱动力在很大程度上是未知的。在此，我们研究肿瘤微环境在肿瘤细胞增殖和功能性的控制中的作用。方法：衍生自非空血管腹部肾组织的调节培养基（CM）用于刺激体外RCC细胞。中和测定用于表征FGF-2在CM中的作用。研究了使用免疫印迹，流式细胞术和免疫荧光显微镜研究CM对RCC细胞的作用的分子机制。最后，为KI-67和P27（KIP1）染色了一系列CCRCC，并且在肿瘤周边和中心分析了表达。结果：我们表明，衍生自rCC相邻的非开始性肾细胞的Cm可以通过以FGF-2依赖性的方式通过增强的蛋白质降解来下调CDK抑制剂P27（KIP1）的表达。 FGF-2主要通过其受体下游的PI3K / AKT路径，并且具有组成型高AKT活性的RCC细胞不仅可以通过EMI1-SKP2轴的增强降解P27（KIP1），而且表明P27的亚细胞错误分析（ KIP1）到细胞质隔室。在体内的肿瘤周边也检测到这种错误定位，表明P27（KIP1）在塑造这种空间的基础中起重要作用。结论：我们的研究结果表明，肿瘤微环境参与通过刺激该区域特征的增强的增殖来塑造肿瘤外周的含量。

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