Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
Cell Metab. 2021 Oct 5;33(10):2021-2039.e8. doi: 10.1016/j.cmet.2021.08.012. Epub 2021 Sep 10.
Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.
透明细胞肾细胞癌（ccRCC）优先侵犯肾周脂肪组织（PAT），这与预后不良有关。然而，这种相互作用的详细机制仍不清楚。在这里，我们描述了 ccRCC 细胞与 PAT 之间的双向通讯。我们发现，ccRCC 细胞分泌甲状旁腺素相关蛋白（PTHrP），通过 PKA 激活促进 PAT 的棕色化，而 PAT 介导的产热导致过量乳酸的释放，从而增强 ccRCC 的生长、侵袭和转移。此外，广泛用于治疗 ccRCC 的酪氨酸激酶抑制剂（TKI）通过促进 PAT 的棕色化，增强了 ccRCC-PAT 通讯的这种恶性循环。然而，如果通过 H89 或 KT5720 抑制脂肪细胞棕色化来短路这种交叉通讯，TKI（舒尼替尼）的抗肿瘤疗效会增强。这些结果表明，ccRCC-PAT 交叉通讯具有重要的临床相关性，联合治疗的应用有望增强 TKI 的疗效。
