Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.
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.
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, Chicago, IL, USA.
Kristin M
KM
Nieman
Hilary A
HA
Kenny
Carla V
CV
Penicka
Andras
A
Ladanyi
Rebecca
R
Buell-Gutbrod
Marion R
MR
Zillhardt
Iris L
IL
Romero
Mark S
MS
Carey
Gordon B
GB
Mills
Gökhan S
GS
Hotamisligil
S Diane
SD
Yamada
Marcus E
ME
Peter
Katja
K
Gwin
Ernst
E
Lengyel
D017667:Adipocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D018920:Coculture Techniques; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009852:Omentum / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary*; D014407:Tumor Cells, Cultured
C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins