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Fat cells in the omentum, a large fatty pad of tissue that drapes over the intestines in the abdomen, fuel the spread of ovarian cancer by providing nutrients and energy for rapid tumor growth, according to a new study published online in Nature Medicine at the weekend.
Study author Ernst Lengyel, professor of obstetrics & gynecology, the University of Chicago, told the press:
"The cells that make up the omentum contain the biological equivalent of jet fuel. They feed the cancer cells, enabling them to multiply rapidly."
He explained that the fatty tissue of the omentum is extraordinarily rich in energy-dense lipids, which provide a "lauching pad" and energy source for ovarian cancer cells, enabling the spread of this lethal disease.
Ovarian cancer is the fifth leading cause of cancer deaths in women, and it tends to spread to the omentum as opposed to distant organs. For the vast majority of women, by the time their ovarian cancer is diagnosed, it has already spread to the omentum, and tumors here often become bigger than the original cancer:
"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," write the authors.
To try and find out more about the role of these fat cells in fuelling ovarian cancer spread, Lengyel and colleagues carried out a series of experiments using ovarian cancer cell cultures and live mice.
When they injected ovarian cancer cells into the abdomens of healthy mice, the cells took only 20 minutes to reach the omentum, showing they find their way there very quickly.
The researchers discovered that adipokines, a type of cell-to-cell signalling protein, inside the omentum were attracting the ovarian cancer cells. When they blocked these signals, the attraction reduced by at least 50%. In their paper they describe what they found:
"... primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and ... adipokines including interleukin-8 (IL-8) mediate these activities."
Once the cancer cells reach the omentum, they immediately set about making the tools that will enable them to make use of the nutrients and energy in the fatty tissue: they even reprogram the fat cells' metabolism to enable the "direct transfer of lipids from adipocytes to ovarian cancer cells".
In culture, the researchers found that the cancer cells also appear to be able to use the fat cells as a source of energy:
"... coculture induced lipolysis in adipocytes and [beta]-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells."
It does not take very long for the cancer to transform the entire omentum into a solid mass of cancer cells.
Lengyel and colleagues discovered that a fatty acid binding protein, FABP4, which transports fat, may be very important to this process and could be a potential target for therapy.
They discovered this when they compared cells from primary ovarian cancer tissue to cells from tumors at the migration sites in the omentum.
They found the cancer cells next to the fat cells in the omentum produced high levels of FABP4, whereas cancer cells that were far away from the omentum fat cells did not produce any.
They showed that inhibiting FABP4 drastically reduced the transport of nutrients from the fat cells to the cancer cells in the omentum. It also slowed down the growth of tumors and their ability to generate new blood vessels.
"FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis," they conclude.
Lengyel and colleagues suggest fat metabolism may also be a factor in other cancers where there is a rich source of fat cells, such as breast cancer. And in the case of FABP4 specifically, it may be implicated in cancers that develop in the abdomen, and therefore:
"... FABP4 emerges as an excellent target in the treatment of intra-abdominally disseminating tumors, which preferentially metastasize to adipose tissue such as ovarian, gastric, and colon cancers."
Funds from the National Institutes of Health, the Burroughs Wellcome Fund, the Committee on Cancer Biology at the University of Chicago and Bears Care, the charitable beneficiary of the Chicago Bears Football Club, helped pay for the study.
Written by Catharine Paddock PhD
