Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

项目摘要 肾细胞癌是最常见的原发肾癌，占原发肾癌的90%-95% 肿瘤。肥胖和糖尿病与患肾癌的风险增加有关，但 全身代谢变化促进肿瘤进展的机制尚不清楚。尽管它的 多年来，作为葡萄糖生产器官的声誉与肝脏、肾脏相比相形见绌 拥有与肝脏相同的糖异生酶补充物-具有更高浓度的 每克肾脏组织中的生糖蛋白，这表明它的生糖能力甚至可能 超过肝脏的。众所周知，葡萄糖是肿瘤生长的关键底物；考虑到葡萄糖异生 肾脏的活性，很可能是肾脏糖异生增加可能会刺激肿瘤的生长。不过，这个 这一现象及其机理解释仍有待探索。我们最近发现成纤维细胞 生长因子-21通过激活肾内脂解促进饥饿时肾糖异生 通过2-肾上腺素能途径，从而激活健康啮齿动物体内的丙酮酸羧化酶流量。因此， 这项提议将检验最重要的假设，即在肾癌中，增加的成纤维细胞生长因子-21作用 通过类似的机制促进肾内脂肪分解，丙酮酸羧基酶活性，结果是， 糖异生，这种增加的肾脏葡萄糖供应促进了肿瘤的生长。我们还将研究 利用成纤维细胞生长因子-21中和抗体治疗遗传性易患肾癌的小鼠。 预期将减少肾脏糖异生和肾细胞癌的进展。如果假设是 经证实，这些数据将确定成纤维细胞生长因子-21-它已经成为先进的临床试验的目标 代谢和糖尿病相关的适应症-作为肾癌的潜在治疗靶点。

Project Summary Renal cell carcinoma is the most common primary kidney cancer, representing 90-95% of primary renal neoplasms. Obesity and diabetes are associated with an increased risk of renal cell carcinoma, but the mechanisms by which systemic metabolic changes promote tumor progression are unknown. Although its reputation as a glucose-producing organ has been dwarfed by that of the liver over the years, the kidney possesses the same complement of gluconeogenic enzymes as the liver – with a higher concentration of gluconeogenic proteins per gram of tissue in the kidney, suggesting that its gluconeogenic capacity may even exceed the liver's. Glucose is well-known to be a crucial substrate for tumor growth; given the gluconeogenic activity of the kidney, it is likely that increased renal gluconeogenesis may fuel tumor growth. However, this phenomenon, and its mechanistic explanation, remains to be explored. We have recently found that fibroblast growth factor-21 (FGF-21) promotes renal gluconeogenesis during starvation by activating intrarenal lipolysis through a 2-adrenergic pathway, thereby activating pyruvate carboxylase flux in healthy rodents. Therefore, this proposal will test the Overarching Hypothesis that in renal cell carcinoma, increased FGF-21 acts through a similar mechanism to promote intrarenal lipolysis, pyruvate carboxylase activity, and as a result, gluconeogenesis, and that this increased renal glucose supply fuels tumor growth. We will also examine the utility of an FGF-21 neutralizing antibody against mice genetically prone to renal cell carcinoma, which we anticipate will reduce renal gluconeogenesis and renal cell carcinoma progression. If the hypotheses are confirmed, these data would identify FGF-21 – which is already being targeted in advanced clinical trials for metabolism- and diabetes-related indications – as a potential therapeutic target in renal cell carcinoma.