Cancer of the ovary has a poor prognosis, generally because it is most often diagnosed at a late stage, when it has already metastasised. Five-year survival rates for this cancer in the UK range from over 90% at Stage I, when the cancer is localised, to only about 6% at Stage IV. Eighty percent of women diagnosed with the most common subtype, serous ovarian cancer, present when the cancer has already spread beyond the ovary to a part of the peritoneum that is termed the omentum. This is a serous membrane, largely composed of adipocytes (fat cells), that extends from the stomach to the bowel; it acts as a storage site for lipids. Metastasis of ovarian cancer to the omentum results in its transformation into a solid tumour almost devoid of adipocytes.

A group of researchers led by Ernst Lengyel at the University of Chicago, Illinois, USA has investigated the molecular mechanisms behind this preference of ovarian tumours to metastasise to the omentum. They first injected fluorescently-labelled SKOV3ip1 human ovarian cancer cells into the peritoneum of female athymic nude mice and showed that within 20 minutes most of the cancer cells had moved to the omentum. Then they proved that both normal human omental adipocytes and medium that had been conditioned by these cells could promote the migration of the ovarian cancer cells.

This activity of the conditioned medium suggested that cancer cell migration was mediated by soluble factors secreted by the adipocytes. Lengyel and his co-workers used a cytokine array both to test this hypothesis and to identify the factors involved. The cells were found to secrete abundantly five out of 62 cytokines tested: IL-6, IL-8, monocyte chemo-attractant protein-1 (MCP-1), tissue inhibitor of metalloproteinases-1 (TIMP-1) and adiponectin, Inhibition all but adiponectin of these using antibodies inhibited the migration of the cancer cells, and inhibition of IL-6 and IL-8 and their receptors reduced the adhesion of the cancer cells to the omentum.

Knowing that adipocytes promote cancer cell growth, Lengyel and his co-workers hypothesised that they do this through the provision of energy-rich lipids. They co-cultured adipocytes with ovarian cancer cells and showed that lipid droplets accumulated within the cytoplasm of these cancer cells. These were shown using fluorescence to have been transferred from the adipocytes, confirming that the fat cells provide lipids to promote cancer cell growth. Furthermore, co-culture altered the metabolism of both cell types, inducing lipolysis in the adipocytes and beta-oxidation in the cancer cells.

The researchers then used protein arrays to compare protein expression in primary cancer cells and omental metastases from 22 women with advanced serous ovarian cancer. Seven of the 10 most up-regulated proteins in the metastases compared to the primary tumour cells were known regulators of cancer cell growth and metabolism. These included a fatty acid binding protein, FAB4, which is highly expressed in adipocytes. This protein was found to be most highly expressed in cancer cells located close to the interface with the omentum. To test the hypothesis that this protein promoted cancer growth, transgenic mice in which its gene had been knocked out (Fabp4^−/− mice) were injected with ovarian cancer cells; tumour growth was significantly reduced in these mice compared to wild type mice. This indicated that this protein is a key to promoting ovarian cancer growth and metastasis to the omentum. Taken together, these results suggest that FABP4 may be a novel target for drugs to prevent metastasis in ovarian and other abdominal cancers.

Reference

Nieman, K.M., Kenny, H.A., Penicka, C.V. and 11 others, Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth, Nature Medicine 17(11), 1498-503, 2011, doi: 10.1038/nm.2492