Lactate: the forgotten cancer master regulator

In 1923 Nobel laureate Otto Warburg observed that cancer cells expressed accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions. His discovery, which is expressed in about 80% of cancers, was named the “Warburg Effect” in 1972 by Efraim Racker. The Warburg Effect in cancer and its role in carcinogenesis has been neither understood nor explained for almost a century. Warburg started the field of cancer metabolism, which became the predominant field in cancer research for several decades after. However, the entire research in cancer took a dramatic turn upon the arrival of genetics when in 1953 Nobel laureates James Watson and Francis Crick discovered the structure of DNA. By the 1980s and onwards, cancer research was fully embedded in the genetics field around the world due to the excitement of genetics and all of its possibilities to cure diseases. In the meantime, cancer metabolism was forgotten and buried at the bottom of the ocean.

Unfortunately, the fight against cancer solely through genetics has probably been one of the biggest mistakes in medical research history, after half a century of research and hundreds of billions of dollars deployed, the cure against cancer through genetics remains elusive and far away from a reality. James Watson himself, who started the fire in cancer genetics, is now criticizing the field for not living up to the expectations, stating that locating the genes that cause cancer has been “remarkably unhelpful”. Watson also acknowledges that targeting cancer metabolism is a more promising avenue than cancer genetics and that if he were to do it over again he would have focused his research on cancer biochemistry and metabolism. In the last 5-10 years, more and more researchers around the world are starting to think like Watson and therefore the field of cancer metabolism is experiencing a renaissance which is believed by many to be the final door to corner and defeat cancer.

However, in order to understand cancer metabolism, it is necessary to go back in time almost a century to what Otto Warburg already tried to tell us. Although the Warburg Effect is seen in the light of excessive and dysregulated glucose consumption, what struck Warburg the most was the aberrant production of lactate from cancer cells which lead Warburg to posit that the etiology of cancer was a mitochondrial injury leading to lactate production. These thoughts were not understood by most scientists during Warburg’s days and a century later most cancer researchers still don’t understand what lactate is.

Nevertheless, back in Warburg’s days, lactate was studied by some of the most prominent scientists of the time. Already in 1857, Louis Pasteur described lactic acid as the result of microbial fermentation due to lack of oxygen. In 1907 Nobel laureate Frederick Hopkins and his colleague Walter Fletcher demonstrated that lactate accumulated when frog muscles were stimulated to contract, and that when fatigued muscles were placed in oxygen-rich environments, lactate disappeared. In 1920 Nobel Laureate Otto Meyerhof identified glycogen precursor to lactate formed in frog muscles electrically stimulated to fatigue with much of the lactate restored to glycogen during aerobic recovery. In 1923 another Nobel Laureate, Archibald Vivian (AV) Hill and his colleague Walter Morley Lupton described the term “O2 Debt” in which they linked lactate production during exercise to oxygen-limited lactate production. Subsequently, Warburg astutely described that lactate production in cancer cells was due to an injury to mitochondria, which we may call today mitochondrial dysfunction. However, neither the knowledge of genetics nor the sufficient technologies to study lactate metabolism were available to Warburg and his contemporaries during his time. Further, because of the stature of the first investigators in lactate, the concept of lactate production as a result of oxygen lack and as a waste product was immortalized in textbooks of physiology and biochemistry for about a century.

However, in the mid-1980s George Brooks from the University of California at Berkeley, decided to unbury lactate from the bottom of the ocean and embarked on a fascinating adventure to understand lactate and its role in skeletal muscle during exercise. Over the years, George Brooks has been able to prove that lactate is not a waste product but a highly active molecule, one of the most important gluconeogenic precursors, a major substrate for almost every cell in the body including the brain or the heart, a major regulator of intermediary metabolism, especially fatty acid metabolism, a highly active signaling molecule with hormone-like properties, and probably even a transcription factor.

When I first read about the Warburg Effect in cancer over two years ago, I was surprised to see that it was not about genetics but about metabolism. Nevertheless, I was more surprised when I saw that it was the main subject of my doctorate thesis although in skeletal muscle, we call it “cytosolic glycolysis” or simply “glycolysis” (under aerobic or anaerobic conditions). The players of glycolysis both in cancer and skeletal muscle are the same except that in cancer cells they are completely dysregulated probably by a primarily genetic dysregulation. In skeletal muscle, however, glycolysis players are perfectly regulated where in fact, despite being the largest structure in the body, skeletal muscle cancer (rhabdomyosarcoma) is rare and due to its embryonal nature it is usually encountered in children accounting only for ~3% of all cancers. The heart, which is the most oxidative form of muscle in the body with a great capacity to uptake lactate, barely ever develops cancer. Angiosarcomas are extremely rare and barely reported clinically as a primary tumor.

As experts in exercise metabolism and especially in glycolysis (“Warburg Effect”), lactate metabolism and skeletal muscle mitochondrial function, Brooks and I decided to take a crack at the Warburg Effect in cancer, and mainly, the role of its obligatory end product, lactate. Through our “Lactagenesis Hypothesis”, we decipher how lactate is probably the only metabolic compound involved and necessary as a master regulator in all main sequela for carcinogenesis. If dysregulated lactate production in glycolytic tumors can be haltered, most forms of cancer could be cured. Accordingly, therapies to limit and disrupt lactate exchange and signaling within, between and among cancer cells should be priorities for discovery.

Featured image credit:  University of  Northern Iowa by Drew Hays. Public domain via Unsplash.