Ovarian tumors are able to co-opt a specific type of adult stem cell from the tissue of the abdomen to enhance its growth, as concluded by research conducted in a collaborative work between the University of Texas MD Anderson Cancer Center and Rice University. The findings of the research, which was recently published in the Cancer Research Journal, may present new ways of targeting severe ovarian cancer through the disruption of the metabolic process.
The investigators focused first on the metabolic differences registered between normal and cancer cells, which were discovered 80 years ago, when the German chemist Otto Warburg discovered that cancer cells transmit more energy due to glycolysis than normal cells, a discovery that led him to win a Nobel Prize. Therefore, scientists worked based on the belief that the “Warbug effect” was verified in all cancers. However, the researchers’ findings suggest that each cancer type has own metabolic signature.
“The presence of a particular type of stem cell known as ‘omental adipose stromal cells,’ or O-ASCs, has been associated with ovarian tumor proliferation, migration and drug resistance, but the exact role of the stem cells was unknown,” explained the lead researcher on the research paper, Deepak Nagrath, from Rice. “We found that O-ASCs supply cancer cells with metabolites they need to produce nitric oxide, a key signaling molecule that is known to increase blood flow.”
In addition, Nagrath is also the director of the Laboratory for Systems Biology of Human Diseases at Rice, which has been focused on analyzing the unique metabolic profiles of diverse cancer types. The team concluded that highly aggressive ovarian cancer cells are dependent of glutamine, as well as when deprived of external sources of it, through the use of experimental drugs, the researchers were able to kill late-stage ovarian cancer cells.
“When we co-cultured the two cell types in the lab, we found that cancer cells used arginine that was secreted by the stem cells, and that the cancer cells, in burning through that arginine, released citrulline, which in turn caused the stem cells to produce more arginine,” said Salimian.
The correlation and dependency between both stem cells and cancer cells seems to release ovarian tumor cells from some of the normal metabolic stresses, allowing it to resist the attacks from chemotherapeutic drugs, as explained by Nagrath. “Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing nitric oxide levels,” he added.
“Significantly, we also found that O-ASC-mediated chemoresistance in cancer cells can be deregulated by altering the balance of nitric oxide that the cancer relies upon,” continued the researcher, who found that a multidrug cocktail may be able to disrupt the stem and cancer cells signals, as it disturbs the metabolic balance that ovarian cancer relies on and enables the growth of metastasis.
“A combined approach of targeting secreted arginine with the enzyme L-arginase, along with targeting microenvironment-secreted factors with the nitric oxide synthesis inhibitor L-NAME may be a viable therapeutic approach for targeting ovarian and endometrial cancers,” he said.
The study, which was funded by Rice’s Ken Kennedy Institute for Information Technology and by Rice’s John and Ann Doerr Fund for Computational Biomedicine, also included Aleksandra Nowicka, a postdoctoral researcher at MD Anderson, Ann Klopp, an assistant professor of radiation oncology at MD Anderson, Ahmad Nabiyar of General Electric Co., Rice graduate student Christine Caneba, and Rice undergraduates Xinran Liu and Kevin Chen.