Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Abstract

Intra-abdominal tumors, such as ovarian cancer1,2, 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.

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…β-oxidation of fatty acids was assessed as previously described, with minor modifications. 2 Briefly, fibroblasts were seeded at a density of 90,000 per well in 24-well plates in complete media and allowed to growth for 2 d. Six replicates were performed for each condition. Fibroblasts were washed with PBS.…”

“…[1][2][3][4][5][6][7][8] Although it is generally agreed upon that cancer cells undergo metabolic re-programming, [1][2][3][4][5][6][7][8] the exact nature of these metabolic changes varies widely, and has not previously been correlated with clinical outcome in cancer patients.…”

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

“…The omentum, the fatty pad of adipose tissue that covers the bowel, is a frequent site of metastasis for ovarian cancer (1)(2)(3). The omentum contains a population of stromal cells, adipose stromal cells (ASC), which are multipotent mesenchymal stem cells that engraft in tumors and can support cancer progression (4-7).…”

Tissu adipeux et cancer

“…Au front invasif des tumeurs mammaires, on retrouve des adipocytes de petite taille correspondant à des CAA ( Figure 4B) et dont le profil de sécrétion est similaire à ce qui a été décrit in vitro dans le modèle de coculture, validant ainsi l'intérêt de ce modèle [16,22]. Ces modifications de la taille et du contenu lipidique des adipocytes sont observées au niveau de la zone de contact entre tissu adipeux et la plupart des tumeurs invasives, comme l'illustre la Figure 4 pour les cancers de la prostate et les mélanomes (données de notre équipe) ou le cancer de l'ovaire avec dissémination péritonéale [23]. Trois grands types de modifications caractérisent donc les CAA.…”

“…• Enfin, la dernière grande caractéristique des CAA est leur délipidation qui semble pour partie dépendante d'un processus de lipolyse conduisant à la libération [23], il a été montré que les acides gras libérés par les adipocytes de l'omentum lors de leur coculture avec les cellules tumorales pouvaient être captés par les cellules cancéreuses, qui les utiliseraient comme source d'énergie via la -oxydation des lipides. Un tel transfert de lipides entre adipocytes et cellules cancéreuses a également été montré dans le cas de cellules tumorales de prostate [29], mais aussi dans le cancer du sein (données non publiées de notre équipe).…”