Abstract IA30: Metabolic symbiosis: The contribution of adipocytes to visceral metastasis
Authors: Nieman Kristin , Ladanyi Andras , Lengyel Ernst 
Published: August 2014

Many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue and are known to reprogram adjacent normal adipocytes into cancer-associated adipocytes (CAA). Clinical observations indicate that the most common, as well as the largest, site of ovarian cancer (OvCa) metastasis is the omentum, a large fat pad (20x12x3cm) positioned in front of the bowel. The omentum, which is primarily composed of adipocytes, provides energy storage and functions as an endocrine organ. Because cancer cell behavior is highly dependent on the microenvironment, and adipocytes are a major source of energy-dense fatty acids, we hypothesized that adipocytes promote OvCa omental metastasis and growth via altered lipid metabolism.

To investigate this hypothesis, primary human visceral adipocytes were cultured from omental tissue specimens collected from patients who underwent surgical procedures for benign conditions. The rate of β-oxidation was assessed by a radioisotopic assay using 3H-palmitate. Sections of human serous ovarian carcinomas and corresponding omental metastases were utilized for immunohistochemistry, RT-PCR, and a reverse-phase protein array. Homozygous fatty acid binding protein 4 (FAPB4)-null mice or wild-type (WT) animals were inoculated orthotopically or intraperitoneally with mouse OvCa cells.

Adipocytes were found to promote the invasion, migration, and proliferation of OvCa cells. The homing of OvCa towards adipocytes in vitro, or to the mouse omentum in vivo, was reduced by using inhibitory antibodies against interleukin (IL)-6,IL-8, or their receptors. Co-culture of OvCa cells with adipocytes resulted in cytoplasmic lipid accumulation in OvCa cells, which was a consequence of direct lipid transfer from the adipocytes. Co-injection of SKOV3ip1 OvCa cells with adipocytes enhanced tumor growth in mice, when compared to the injection of SKOV3ip1 cells alone. Moreover, lipolysis was activated in co-cultured adipocytes as evidenced by the secretion of free fatty acids and glycerol. FABP4 was found to be highly expressed in omental metastatic tissues as compared to the respective primary OvCa tumor tissue. When mouse OvCa cells were injected under the ovarian bursa of FABP4 knock-out mice the number of metastases was significantly lower than in WT mice. Treatment with a FABP4 inhibitor also induced apoptosis and inhibited migration and invasion of OvCa cells. The fatty acid translocase (FAT/CD36) was identified as the fatty acid transporter responsible for lipid accumulation in cancer cells co-cultured with adipocytes.

Our results suggest that adipocytes advance the progression of OvCa through two major mechanisms: (1) They promote metastasis to the omentum via the secretion of cytokines, and (2) They support cancer cell proliferation by activating lipolysis, thereby mobilizing energy-dense fatty acids which are utilized by the cancer cells in an energy-yielding β-oxidation pathway through a FABP4 and FAT/CD36 dependent mechanism. By better understanding these mechanisms and, more generally, the biology of adipocytes in the tumor microenvironment, we will be able to identify metabolic targets and, ultimately, introduce new compounds for the treatment of cancer.

Citation Format: Kristin Nieman, Andras Ladanyi, Ernst Lengyel. Metabolic symbiosis: The contribution of adipocytes to visceral metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA30.