Adipokine Apelin/APJ Pathway Promotes Peritoneal Dissemination of Ovarian Cancer Cells by Regulating Lipid Metabolism

Ovarian cancer is among the most prevalent cancers in the female population. Moreover, those living with obesity or metabolic disorders are more likely to develop cancers. It is also now well-known that adipose tissues secrete various inflammatory mediators. Visceral fat tissues rich in adipocytes are one of the most significant sources of adipokines and other inflammatory mediators and chemotactic proteins.

High-grade serous ovarian carcinoma (HGSOC) is the most common type among various ovarian cancers and particularly associated with poor outcomes and low 5-year survivability rates. Advanced HGSOC are highly metastatic due to frequent peritoneal dissemination. Ovarian cancer tends to spreads to the fat-rich tissues, called the omentum within abdominal cavity. Studies showed that cancer cells use lipids acquired from fat cells to generate much-needed energy for rapid tumor progression and excessive lipid accumulation within cancer cells is a hallmark for cancer aggressiveness.

Recently researchers found that high expression of apelin receptors (APJ) on cancer cells is associated with faster ovarian cancer progression and poorer outcomes. Activation of APJ receptors results in greater dissemination of cancer cells. Adipokine apelin, secreted by adipocytes, activates APJ receptors, explaining why greater obesity may be adversely associated with ovarian cancer outcomes. These pathways play an important role in the development of diabetes, energy metabolism, cardiovascular regulation, and numerous other physiological processes.

In a new study led by Professor Sukyung Woo from University at Buffalo investigated the mechanisms of how adipokines promote the apelin/APJ pathway and result in faster dissemination of ovarian cancer.  The original research article is now published in the Journal of Molecular Cancer Research.

The research team cultured adipocytes along with ovarian cancer cells in a culture media. The adipocytes secret high level of apelin in the culture media. The authors found that high apelin expression resulted in the more significant proliferation and dissemination of the cancer cells. This higher migration rate plays a central role in the increased risk of metastasis. Moreover, they also found how apelin-APJ activation affected the energy metabolism of ovarian cancer cells. Higher apelin expression and greater APJ receptor activation resulted in a higher accumulation of lipid droplets in the ovarian cancer cells. It means that apelin-APJ activation ultimately results in a greater energy supply for the cancer cells. The apelin expression resulted in a four times increase in cancer cell migration. However, such an increase in cancer cells migration was not seen in control media, thus confirming the role of apelin. Further, the study explored the role of the apelin-APJ pathway in ovarian cancer adhesion to the omentum. They found that cancer cells activated by apelin had about 5 times greater adhesion rate to the omentum. Moreover, these cells cocultured with adipocytes were more invasive, thus confirming the role of apelin in increasing the invasiveness of ovarian cancer cells. When the authors tried to block this pathway, they found this phenomenon can be reversed by APJ inhibition which can be achieved using the APJ antagonist, F13A.

In a nutshell, the new study demonstrated that greater apelin expression by adipose tissues and higher expression of APJ receptors in specific ovarian cancer cells results in better lipid intake by cancer cells, increased energy supply, and thus better survival, fitness and dissemination of these cells resulting in metastasis of cancer. It also demonstrated the role of apelin-APJ pathway in increasing ovarian cancer cell adhesion and invasiveness. The study not only demonstrated how the apelin-APJ pathway results in better utilization of energy by cancer cells and increased uptake of lipids by these cells. It also showed that blocking this pathway is possible, reducing the risk of cancer metastasis and thus improving the efficacy of chemotherapy targeted at ovarian cancer.