The Prime and Integral Cause of Cancer in the Post-Warburg Era

SIMPLE SUMMARY: In this perspective, we have gone back to the beginnings of metabolic cancer research to grow from its roots. From the time of Otto Warburg, the field of cancer research has progressively learned the fundamental importance of metabolism. In this contribution, we also clarify the errors committed along the way to reaching the present state of the art. Nowadays, a multitude of intermediary causes of cancer have been identified that are shown to act through final and integral causes. This new conceptualization allows a better understanding of the mechanisms working behind the famous Warburg effect. At the same time that the initial limitations and misinterpretation of this effect are considered, we also explain its origin through the lens of the pH-related cancer paradigm. Here it is also shown that nowadays this hydrogen ion (H(+))-mediated perspective is key to understanding the role of the pH-approach as the prime and sine que non metabolic cause of cancer. ABSTRACT: Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H(+)), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO(2) led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.