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Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis.
Oncogene ( IF 8 ) Pub Date : 2018-Apr-01 , DOI: 10.1038/s41388-017-0093-z
Andras Ladanyi , Abir Mukherjee , Hilary A. Kenny , Alyssa Johnson , Anirban K. Mitra , Sinju Sundaresan , Kristin M. Nieman , Gloria Pascual , Salvador Aznar Benitah , Anthony Montag , S. Diane Yamada , Nada A. Abumrad , Ernst Lengyel

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

中文翻译:

脂肪细胞诱导的CD36表达驱动卵巢癌的进展和转移。

卵巢癌(OvCa)的特征是腹膜腔内广泛而快速的转移。内脏脂肪细胞通过提供用于肿瘤生长的脂肪酸(FA)来促进这一过程。但是,FA从脂肪细胞转移到癌细胞的确切机制仍然未知。这项研究表明,与原代人网膜脂肪细胞共培养的OvCa细胞在质膜中表达高水平的FA受体CD36,从而促进外源FA的摄取。使用CD36抑制剂和短发夹RNA抑制作用剥夺OvCa细胞脂肪细胞衍生的FA阻止了脂肪细胞诱导的恶性表型的发展。具体而言,CD36的抑制作用减弱了脂肪细胞诱导的胆固醇和脂质滴的积累,并降低了细胞内活性氧(ROS)的含量。代谢分析表明,CD36在富含脂肪细胞的微环境中对OvCa细胞的生物能适应起着至关重要的作用,并控制着它们的代谢可塑性。此外,CD36的缺失会影响在腹膜传播中起因果作用的细胞过程,包括粘附,侵袭,迁移和锚定独立生长。腹膜内注射CD36缺陷型细胞或用抗CD36单克隆抗体治疗可减轻小鼠异种移植物中的肿瘤负担。此外,原发性和转移性人类卵巢肿瘤的匹配队列显示转移组织中CD36的上调,这一发现在三个公共基因表达数据集中得到了证实。这些结果表明,网膜脂肪细胞通过OvCa细胞中CD36的上调来重编程肿瘤代谢。
更新日期:2018-02-05
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