Normal cells produce energy through the process of oxidative phosphorylation, whereas cancer cells typically produce energy through glycolysis and lactic acid fermentation. Although glycolysis is less efficient than oxidative phosphorylation, the increased production of metabolites is beneficial to proliferating cells.

This process, called the Warburg effect, named after Nobel laureate Otto Warburg, who discovered the phenomenon. It occurs in tumor cells when glucose uptake is increased and lactate is produced even in the absence of oxygen and fully functioning mitochondria (requirements for oxidative phosphorylation, a more efficient process).

However, the exact nature of the Warburg effect in cancer metabolism remains a mystery. In 2017, the author of the current study, Iñigo San Millán, PhD, an assistant professor of medicine at the University of Colorado School of Medicine and the University of Colorado Colorado Springs, proposed the lactagenesis hypothesis, which suggests that the predominant role of lactate in cancer is to fuel both cancer biomass growth and carcinogenic signaling. Specifically, lactate is used for angiogenesis, immune escape, cell migration, metastasis, and self-sufficient metabolism.

In breast cancer, an average of 33 somatic mutations with several key driver genes confer tumor growth. Therefore, in the current study, the researchers explored whether endogenous or exogenous lactate acts as an oncometabolite that affects the transcription of key driver genes (oncogenes) in breast cancer (specifically MCF7, a human breast cancer cell line).

Lactate's role in carcinogenesis

The results of the cell studies revealed that lactate increased expression of the oncogenes between 150% and 800%. Moreover, the results show that lactate can be produced in the presence of oxygen, and it does alter the transcription of oncogenes. Lactate was a regulator of cyclin-dependent kinases, which are overexpressed in the presence of lactate and cause dysfunctional cell cycle, leading to carcinogenesis.

Overall, the researchers concluded that lactate acts as an oncometabolite capable of regulating transcriptional activity of key oncogenes, transcription factors, tumor suppressors, and cell cycle genes involved in breast cancer.

"We discovered that lactate is a catalyst that triggers a mechanism in mutated cells necessary to continue the cancer-forming process," San Millán said. "This opens a new door to better understand cancer at the metabolic level. It also means we might be able to target lactate with new therapies."

The researchers are exploring the reproducibility of their theory in other cancers like small-cell lung cancer and are finding similar results.

Lactate therapy options

As one way of limiting the carcinogenic effect of lactate, San Millán and his team are exploring exercise. Muscle tissue is resistant to carcinogenesis, as lactate is cleared from muscle fibers during and after exercise. Alternatively, lactate produced in cancer is not rapidly cleared and is highly concentrated in the cancer microenvironment. Therefore, personalized exercise programs may have the potential to help prevent and treat cancer.

"Lactate, which used to be considered a waste product, turns out to be a major signaling molecule and a major regulator of the genes involved in cancer," San Millán said. "This is not the same behavior of lactate we get from doing exercise because that is quickly removed by the muscles and has positive signaling properties to improve physical fitness. The lactate produced in cancer stays put, is constantly being produced, and acts as a catalyst to activate mutated genes into cancer. We still don't know these mechanisms, but we are investigating them now."

The researchers are also exploring methods of blocking lactate from leaving cancer cells, thereby eliminating their carcinogenic effects.

"When lactate is produced, it has to leave the cell through a transporter," San Millán said. "We are trying to block the transporter as well as lactate production inside the cancer cell with different compounds. If you block the door, the lactate cannot leave and the cancer cell will burst."

This treatment option would require extremely targeted therapies, and the team is beginning to test potential lactate blockers in mice.

"If we can effectively target lactate," San Millán said, "we could possibly be taking a great step toward ending cancer."

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