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性肾癌，占原发性肾癌的90-95%。 肿瘤。肥胖和糖尿病与肾细胞癌的风险增加有关， 全身代谢变化促进肿瘤进展的机制尚不清楚。虽然其 多年来，作为一个产生葡萄糖的器官，肾脏的声誉与肝脏相比相形见绌， 具有与肝脏相同的致炎酶的补充-具有更高浓度的 肾脏中每克组织中的致炎蛋白，这表明其致炎能力甚至可能 超过了肝脏。众所周知，葡萄糖是肿瘤生长的关键底物;考虑到肿瘤的发生， 由于肾脏的活动增加，因此增加的肾脏肿瘤发生可能促进肿瘤生长。但这 这一现象及其机制解释仍有待探索。我们最近发现成纤维细胞 生长因子-21（FGF-21）通过激活肾内脂肪分解促进饥饿期间的肾再生 通过β 2-肾上腺素能途径，从而激活健康啮齿动物中的丙酮酸羧化酶通量。因此，我们认为， 这项提议将检验在肾细胞癌中FGF-21的增加， 通过类似的机制促进肾内脂解、丙酮酸羧化酶活性，结果， 肾脏葡萄糖供应的增加促进了肿瘤生长。我们亦会研究 利用FGF-21中和抗体对抗遗传上易患肾细胞癌的小鼠， 预期将减少肾肿瘤的发生和肾细胞癌的进展。如果假设是 证实，这些数据将确定FGF-21 -这已经是在先进的临床试验的目标， 代谢和糖尿病相关适应症-作为肾细胞癌的潜在治疗靶点。

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.