Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mol Cancer Res. 2020 Sep;18(9):1414-1426. doi: 10.1158/1541-7786.MCR-20-0364. Epub 2020 Jun 3.
Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of and modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma promotes tumor proliferation, invasion, and metastasis, but how stromal lipids influence these processes remain to be defined. Here, we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation. Stromal cells lacking CAVIN1 enhance prostate cancer cell migration and invasion. Remarkably, they increase lipid uptake and M2 inflammatory macrophage infiltration in the primary tumors and metastasis to distant sites. Our data support the concept that stromal cells contribute to prostate cancer aggressiveness by modulating lipid content and inflammation in the tumor microenvironment. IMPLICATIONS: This study showed that stromal CAVIN1 suppresses prostate cancer metastasis by modulating tumor microenvironment, lipid content, and inflammatory response.
脂质摄取通过 caveolae 发生，caveolae 是由 caveolins (CAV) 和 caveolae 相关蛋白 1 (CAVIN1) 形成的质膜内陷。和的基因改变改变了脂质代谢，并为脂肪营养不良综合征提供了基础。脂质通过为癌症代谢提供燃料和支持生长和信号转导来促进肿瘤发生。肿瘤基质促进肿瘤增殖、侵袭和转移，但基质脂质如何影响这些过程仍有待确定。在这里，我们表明基质 CAVIN1 调节前列腺癌微环境中的脂质丰度并抑制转移。我们表明，前列腺基质细胞中 CAVIN1 的耗竭会显著减少其脂滴积累并增加炎症。缺乏 CAVIN1 的基质细胞增强了前列腺癌细胞的迁移和侵袭。值得注意的是，它们增加了原发性肿瘤和远处转移部位的脂质摄取和 M2 炎症性巨噬细胞浸润。我们的数据支持这样一种观点，即基质细胞通过调节肿瘤微环境中的脂质含量和炎症反应来促进前列腺癌的侵袭性。
本研究表明，基质 CAVIN1 通过调节肿瘤微环境、脂质含量和炎症反应来抑制前列腺癌转移。
