Department of Pathology, Stanford University, Stanford, CA 94305, USA.
TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan.
Sci Immunol. 2024 Oct 18;9(100):eadg6453. doi: 10.1126/sciimmunol.adg6453.
Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell-derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.
肥胖个体中，多种癌症（包括结直肠癌）更常见且通常更具侵袭性。在此，我们发现肥胖症和结直肠癌患者的肿瘤内以及肥胖症结直肠癌小鼠的肿瘤内积累了巨噬细胞，并促进了肿瘤的加速生长。这些变化是由油酸积累以及随后的肿瘤细胞源性酸产生引发的，由巨噬细胞通过酸感应受体 GPR65 信号驱动。我们在肥胖小鼠的肝细胞癌（HCC）中发现了 GPR65 类似的作用。肥胖症患者的结直肠癌或 HCC 肿瘤也表现出 GPR65 表达增加，这表明此处揭示的机制可能有助于一系列与肥胖相关的癌症中的肿瘤生长，并代表一个潜在的治疗靶点。
