Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, Chicago, IL, USA.
Nat Med. 2011 Oct 30;17(11):1498-503. doi: 10.1038/nm.2492.
Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
腹腔内肿瘤，如卵巢癌，有明确的倾向转移到大网膜，一个主要由脂肪细胞组成的器官。目前，尚不清楚为什么肿瘤细胞优先归巢并在大网膜中增殖，但大网膜转移通常代表卵巢癌女性腹腔内最大的肿瘤。我们在这里表明，原代人网膜脂肪细胞促进了卵巢癌细胞的归巢、迁移和侵袭，脂肪细胞因子，包括白细胞介素-8（IL-8），介导这些活性。脂肪细胞-卵巢癌细胞共培养导致脂肪细胞中的脂质直接转移到卵巢癌细胞，并促进了体外和体内肿瘤生长。此外，共培养诱导脂肪细胞中的脂肪分解和癌细胞中的β-氧化，表明脂肪细胞是癌细胞的能量来源。蛋白质芯片鉴定出与原发性卵巢肿瘤相比，大网膜转移中脂肪酸结合蛋白 4（FABP4，也称为 aP2）的上调，并在脂肪细胞-肿瘤细胞界面检测到卵巢癌细胞中的 FABP4 表达。FABP4 缺乏显著削弱了小鼠的转移性肿瘤生长，表明 FABP4 在卵巢癌转移中具有关键作用。这些数据表明脂肪细胞为快速肿瘤生长提供脂肪酸，确定脂肪代谢和转运为脂肪细胞是微环境主要组成部分的癌症的新治疗靶点。
