Adipose tissue, which can provide adipokines and nutrients to tumors, plays a key role in promoting ovarian cancer metastatic lesions in peritoneal cavity. The adipokine apelin promotes ovarian cancer metastasis and progression through its receptor APJ, which regulates cell proliferation, energy metabolism, and angiogenesis. The objective of this study was to investigate the functional role and mechanisms of the apelin-APJ pathway in ovarian cancer metastasis, especially in context of tumor cell–adipocyte interactions. When co-cultured in the conditioned media (AdipoCM) derived from 3T3-L1 adipocytes, which express and secrete high apelin, human ovarian cancer cells with high APJ expression showed significant increases in migration and invasion in vitro . We also found that cells expressing high levels of APJ had increased cell adhesion to omentum ex vivo , and preferentially “home-in” on the omentum in vivo . These apelin-induced pro-metastatic effects were reversed by APJ antagonist F13A in a dose-dependent manner. Apelin-APJ activation increased lipid droplet accumulation in ovarian cancer cells, which was further intensified in the presence of AdipoCM and reversed by F13A or APJ knockdown. Mechanistically, this increased lipid uptake was mediated by CD36 upregulation via APJ-STAT3 activation, and the lipids were utilized in promoting fatty acid oxidation via activation of AMPK-CPT1a axis. Together, our studies demonstrate that adipocyte-derived apelin activates APJ-expressing tumor cells in a paracrine manner, promoting lipid uptake and utilization and providing energy for ovarian cancer cell survival at the metastatic sites. Hence, the apelin-APJ pathway presents a novel therapeutic target to curb ovarian cancer metastasis. Implications: Targeting the APJ pathway in high-grade serous ovarian carcinoma is a novel strategy to inhibit peritoneal metastasis.

中文翻译：

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脂肪因子 Apelin/APJ 通路通过调节脂质代谢促进卵巢癌细胞的腹膜播散

脂肪组织可以为肿瘤提供脂肪因子和营养物质，在促进卵巢癌腹腔转移性病变中起关键作用。脂肪因子 apelin 通过其调节细胞增殖、能量代谢和血管生成的受体 APJ 促进卵巢癌的转移和进展。本研究的目的是研究 apelin-APJ 通路在卵巢癌转移中的功能作用和机制，特别是在肿瘤细胞 - 脂肪细胞相互作用的背景下。当在来自 3T3-L1 脂肪细胞的条件培养基 (AdipoCM) 中进行共培养时，其表达和分泌高 apelin，具有高 APJ 表达的人卵巢癌细胞在体外显示出迁移和侵袭显着增加。我们还发现，表达高水平 APJ 的细胞离体与网膜的细胞粘附增加，并且在体内优先“归巢”在网膜上。APJ拮抗剂F13A以剂量依赖性方式逆转了这些apelin诱导的前转移作用。Apelin-APJ 激活增加了卵巢癌细胞中的脂滴积累，在 AdipoCM 存在下进一步加剧，并被 F13A 或 APJ 敲低逆转。从机制上讲，这种增加的脂质摄取是由通过 APJ-STAT3 激活的 CD36 上调介导的，并且脂质被用于通过激活 AMPK-CPT1a 轴来促进脂肪酸氧化。总之，我们的研究表明，脂肪细胞衍生的 apelin 以旁分泌方式激活表达 APJ 的肿瘤细胞，促进脂质摄取和利用，并为转移部位的卵巢癌细胞存活提供能量。因此，apelin-APJ 通路为抑制卵巢癌转移提供了一种新的治疗靶点。启示：针对高级别浆液性卵巢癌的 APJ 通路是一种抑制腹膜转移的新策略。