A team from the Los Angeles-based Terasaki Institute for Biomedical Innovation has identified the key role of a metabolic enzyme in ovarian cancer metastasis. The enzyme, glucose-6-phosphate dehydrogenase (G6PD), promotes cancer growth and metastasis development in the omentum, a plica of fatty tissue located in the abdominal cavity. These new data, presented in Cell Reports, also confirm the role of fatty acids as fuel for tumors.
Ovarian cancer cells aggressively migrate and proliferate in this epiploic fold of fat, metabolizing fatty acids and using them as fuel. In this process, and through the identified G6PD pathway, harmful oxidative compounds accumulate, further promoting cancer cell growth.
G6PD, a key enzyme, a promising therapeutic target
By identifying this role of G6PD, the study helps explain the rapid progression of ovarian cancer, a particularly lethal metastatic disease in which 80 percent of patients are diagnosed at stage III or higher. The prognosis of this cancer is therefore very poor, with a 5-year survival rate of about 30 percent. Aggressive migration and spread of tumor cells in the omentum is well documented and with good reason, as this adipose tissue provides the tumor with fatty acids as a fuel source.
Genetic and metabolic analyses revealed that this increase in fatty acid metabolism of tumor cells induces the production of oxidative compounds, which increase the level of oxidative stress in the tumor microenvironment and impair tumor cell metabolism. G6PD counteracts the effects of this oxidative stress and promotes metabolism and thus metastasis in the omentum.
Therefore, elevated levels of oxidative compounds and metabolites are observed in omentum metastases compared with primary tumors. Similar observations have been made in mouse models of ovarian cancer and in tumor cell lines and organoids cultured with omental tissue.
When researchers inhibit G6PD through gene silencing or pharmacological inhibition, they observe tumor cell death, particularly in media conditioned to be “epiploic.” These results suggest that G6PD expression is necessary for tumor development and metastasis. The same result was obtained in mouse models of ovarian cancer: the mice treated with a G6PD inhibitor drug developed fewer metastatic tumors in the omentum.
G6PD is an important component that compensates for the oxidative stress created by fatty acid metabolism by cancer cells in the omentum. Without this enzyme, metastatic cells die due to oxidative stress. This new understanding of the metabolic process that influences tumor survival, growth, and metastasis reveals a new therapeutic target for this poor prognosis cancer.