CANCER! Media buzzword, devastating disease, hot research topic. The scientific research community is constantly churning out new discoveries in an effort to revolutionize our means of attack against cancer, ranging from immunology to gene therapy. While these advancements have seen a variety of success, researchers continue to look further toward the innovative, believing that they have exhausted their use of the principles of cancer biology as a means of targeting cancer. Yet, a new discovery plans to take us all back to the basics.
Researchers from the Children’s Medical Center Research Institute at UT Southwestern did not expect to entirely reverse traditional thinking on cancer cell growth, but their discovery offers promising insight into the future of cancer therapeutics.
By investigating the metabolism of non-small-cell lung cancer, these researchers revealed that lactate, a molecule formerly thought to be a waste product of cancer cell metabolism, acted as a source of carbon for these cells, allowing the cancer to feed off of the lactate and promote further growth.
Dating back to 1927, cancer biologist Otto Warburg examined the environmental factors that allowed cancer cells to grow, along with any biproducts produced from their metabolism. His studies showed three common properties seen in rapidly-growing cancer cells:
• Increased consumption of glucose
• Use of alternate metabolic pathways for glucose processing in anaerobic (oxygen-lacking) environments
• Secretion of lactate as a waste product
This discovery, dubbed the Warburg effect, would go on to frame cancer metabolism research for years to come, encouraging scientists to focus on the mechanisms of metabolism as they relate to the processing and conversion of glucose to energy. This is the case with the development of trimetazidine and ranolazine, popular therapies which prevent processing of various food molecules in the mitochondria, especially lipids. Advancements using these parameters have developed into effective therapeutics to treat cancers, yet it has also left investigation into lactate’s role in cancer cell growth largely uninvestigated.
Lactate, a molecule formerly thought to be a waste product of cancer cell metabolism, acted as a source of carbon.
In time, many began to question the validity of the Warburg effect, conducting studies that would begin to reorient researchers’ mindsets on cancer cell metabolism. One such precursor study from early 2017, conducted by a research team including Princeton University professor Dr. Yibin Kang, wanted to reinvestigate the possibility of molecules other than glucose being consumed by cancer cells to grow, leading to an increased interest in molecules such as lactate which disprove, in part, the Warburg effect.
In targeting metabolism of breast cancer cells, the research team identified an increased activity of LDHA, the protein that converts one starting molecule in metabolism, pyruvate, to lactate, indicating that these cancer cells are potentially using lactate to grow and metastasize by spreading to other organs in the body.
The research team from UT Southwestern took this discovery a step further, establishing that cancer cells are directly metabolizing lactate as a source of energy instead of solely converting pyruvate into lactate.
“We were completely shocked by our findings,” said Dr. Ralph DeBerardinis, whose lab carried out the study. “Cancer metabolism is clinically actionable, and understanding the lactate pathway could help us find therapeutic targets for lung cancer. Lactate uptake could also have predictive value when used as an imaging tracer.”
While DeBerardinis admits the preliminary state of this study, he acknowledges the strength of its results and the encouragement it provides for the future of therapeutics that target metabolism.
With this paradigm shift in the scientific community’s perspective on cancer cell metabolism and the Warburg effect, we can expect greater therapeutic drugs to arise in the coming years. Insofar, therapeutic research has exhausted its modes of attacking cancer cells as they have been relegated to investigating the role of glucose in metabolism. This research focus can only be taken so far by inhibiting mitochondrial function or blocking the glucose from being consumed.
After having seen lactate’s use as an energy source in both breast and lung cancers, researchers can begin to confidently investigate the connection between creating lactate as a waste product and consuming it for cell growth and metastasis, opening up another avenue for targeting cancer cells and taking us one step closer to developing new treatments for such a debilitating disease.