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

Kristin M. Nieman, Hilary A. Kenny, Carla V. Penicka, Andras Ladanyi, Rebecca Buell-Gutbrod, Marion R. Zillhardt, Iris L. Romero, Mark S. Carey, Gordon B. Mills, Gökhan S. Hotamisligil, S. Diane Yamada, Marcus E. Peter, Katja Gwin, Ernst Lengyel

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958 Scopus citations

Abstract

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 Î 2-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.

Original languageEnglish (US)
Pages (from-to)1498-1503
Number of pages6
JournalNature medicine
Volume17
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Nieman, K. M., Kenny, H. A., Penicka, C. V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M. R., Romero, I. L., Carey, M. S., Mills, G. B., Hotamisligil, G. S., Yamada, S. D., Peter, M. E., Gwin, K., & Lengyel, E. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature medicine, 17(11), 1498-1503. https://doi.org/10.1038/nm.2492