Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.
Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.
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腹内肿瘤，如卵巢癌，有明显的大网膜转移倾向，大网膜是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聚集在大网膜并在其中增殖，但大网膜转移通常是卵巢癌女性腹部最大的肿瘤。我们在这里表明，原代人大网膜脂肪细胞促进卵巢癌细胞的归巢、迁移和侵袭，包括白细胞介素8(IL-8)在内的脂肪因子介导了这些活动。脂肪细胞-卵巢癌细胞共培养可直接将脂肪细胞中的脂肪转移到卵巢癌细胞，促进肿瘤的体内外生长。此外，共培养诱导了脂肪细胞的脂解和癌细胞的β氧化，表明脂肪细胞是癌细胞的能量来源。与原发卵巢肿瘤相比，蛋白质阵列发现脂肪酸结合蛋白4(FABP4，也称为aP2)在大网膜转移瘤中表达上调，FABP4在脂肪细胞-肿瘤细胞界面的卵巢癌细胞中检测到表达。FABP4基因缺失显著损害了小鼠转移性肿瘤的生长，表明FABP4在卵巢癌转移中起关键作用。这些数据表明，脂肪细胞为肿瘤的快速生长提供脂肪酸，将脂肪代谢和运输确定为治疗癌症的新靶点，其中脂肪细胞是微环境的主要组成部分。
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.