When compared to normal cells, cancer cells have highly acidic environments. Reducing this acidity is therefore the key to fighting cancer cells and cancer tumors (Acid/base balance, 2008). In fighting the acidity, it appears that oxygen must play some role in determining the acid levels found in malignant cancerous cells since it has traditionally been assumed that absence of oxygen frustrates the ability of susceptible cells to use the Krebs Cycle to produce ATP. Consequently, those cells utilize glucose fermentation for their chief source of energy – and this process results in inordinately high levels of lactic acid being produced. Dr. Warburg was the first to suggest that there was a correlation between lack of oxygen and a general by-passing of the Citric Acid Cycle.
Research has indicated that a hypoxia-induced switch is found from mitochondrial respiration to glycolysis. There is also a metabolic reprogramming because of loss-of-function of enzymes such as fumarate and succinate dehydrogenases (Kroemer, 2006). These facts provide tentative support for the idea that increased oxygen means greater resistance to the cancerous cells which cause mutations and deadly tumors. A Fox Chase Cancer Study found that hypoxia in tumor cells correlates with tumor aggressiveness (Chiarotto & Hill, 1999; Lash et al., 2002; Buchler et al., 2003). Further research reveals that within the majority of solid tumors are areas of low oxygen or dead tissue (Glycolysis, 2007). In essence, Dr. Warburg’s contention that oxygen levels directly determine whether or not cancerous cells will multiply in a human patient seems to be substantiated by recent literature. Additional research confirms that the oxygen levels in growing tumors are critically low; at the same time, low levels of oxygen mean that cancerous cells depend for their survival upon anaerobic dissimilation. Ultimately, this implies that mammalian cells cannot ferment fatty acids, and that vivo tumor cells depend exclusively upon glucose fermentation (Bongaerts et al, 1213).
With regards to renal cancer, other important facts also emerge that largely substantiate the impression that oxygen-independent energy production is part of what is needed in order for cancer cells to survive. According to one study, renal cancer cells display a “bioenergetic shift toward non-oxidative glucose fermentation in progressing tumors”. In another passage, it is mentioned that “anaerobic glucose fermentation to lactate (aerobic glycolysis) leading to oxygen- and mitochondria- independent ATP generation is a hallmark of aggressive cancer growth” (Langbein et al, 2422).
Having devoted some initial attention to highlighting how oxygen levels contribute to the aggravation of diminishment of cancer, it is now appropriate to look more closely at the work of Dr. Warburg himself. Warburg held that the main cause of cancer is the respiration of oxygen in normal body cells being replaced by a fermentation of sugar. He has also noted that cancer cells require glucose fermentation in order to survive. Without question, Warburg’s own research results are an early indicator that the absence of oxidative dissimilation (as brought about by lack of oxygen) leads directly to anaerobic dissimilation involving glucose fermentation. It can now be concluded that lack of oxygen eventually causes the sort of glucose fermentation or anaerobic glycolysis that makes it possible for cancer cells to grow.
Analysis of the available research leads one to the conclusion that Dr. Warburg was correct in his original hypothesis. Hypoxia is not only vital to cancerous growth but more especially to the initiation of cancerous growth. Of course, various researchers have argued that because cancer cells demonstrate a pronounced dependence on glycolytic pathway for ATP generation, this provides a biochemical basis for the development of therapeutic strategies to preferentially destroy cancer cells through pharmacological inhibition of glycolysis. One therapeutic option consists of reversing hypoxic conditions via oxygen introduction whereas new drugs might be a possible alternative (Pelicano et al., 2006). There is certainly no reason to discount this – but such assertions do not in any way diminish Warburg’s general argument that hypoxia is the main reason why the sort of anaerobic glycolysis which permits cancer cells to flourish exists at all.
Warburg’s findings contain far-reaching significance. Increasing oxygen flow – even if it is insufficient by itself in successfully combating cancer – is one part of stopping tumor cells from growing more and more populous within the body of a human being. Among his other findings, Dr. Warburg revealed that the increased conversion of glucose to lactic acid – something associated with a general impairment of mitochondrial respiration – is a significant feature of tumors. This increase in glucose conversion actually appears to shed some light on why cancer cells appear to resist environmental changes that would seemingly discourage glycolysis and encourage oxidative phosphorylation. Studies indicate that cancer cells display a dependency on glycolysis that leads the cells in question to up-regulate the pathway to a significant degree once their respiration was inhibited. At the same time, however, cancer cells which have been studied – at least by one group of researchers – were attenuated in oxidative phosphorylation (OXPHOS) capacity and were found to be unable to adequately up-regulate mitochondrial OXPHOS once glycolysis was disabled. The observed mitochondrial impairment was found to be intimately associated with the increased dependency on glycolysis (Wu et al., 2007). Such studies demonstrate that while normal tissues rely upon oxygen-dependent organelles (specifically, mitochondria) for ATP creation, cancerous cells do not rely nearly so heavily upon mitochondrial activity and simply accommodate themselves to the production of metabolic energy through glucose conversion into lactic acid (Pedersen, 2007). The concept of mitochondrial impairment in cancerous cells is also discussed at length by Modica-Napolitano, et al., 2007). All of these findings have implications for our understanding of Dr. Warburg’s conclusions.
Dr. Warburg’s findings should be interpreted as follows: cells which lack appropriate access to oxygen are at increased risk for cancer and will eventually metastasize into cancerous cells. Whereupon they will become dependent upon anaerobic glycolysis so that they will be unable to respond in a manner that ensures the up-regulation of mitochondrial OXPHOS even when environmental factors discouraging glycolysis are introduced. Warburg’s linkage of cancer initiation with oxygen deprivation – and the subsequent support of this contention by the medical literature – should not be interpreted as a signal that the key to fighting cancer can be neatly reduced to changing one environmental variable (oxygen). The correct implication is that oxygen levels might be the priority for researchers and physicians in oncology. Today, a great deal of the research tends to look at structural factors within the cancerous cell that make cellular growth possible in tumors. One of the more important discoveries of recent years is that the M2 splice isoform of pyruvate kinase is critical to tumor growth and to successful cellular metabolism (Christofk et al., 2008).
From this discussion it is clear that hypoxia plays a vital role in cancer propagation and procreation. What is less clear is whether or not oxygenation alone is sufficient to overcome cancerous tumors. Although further research is still needed, it does appear that oxygenation is best utilized when it is a part of a diverse approach. At the very least, Dr. Warburg’s contention that oxygen levels are a prime indicator of the susceptibility of tissue to cancer, onset is borne out by what other scholars have frequently noted since his path-breaking work in the 1920s. There is also every indication that hypoxia can complicate treatment, as well. Complications occur because hypoxic cells are an obstacle to successful cancer treatment insofar as these cells are protected from the countering cytotoxic effects of radiotherapy and many anti-cancer drugs (Teicher et al. 1995).
It may seem unduly self-evident that a clear lack of oxygen does expedite and even facilitate the transition to anaerobic glycolysis and glucose fermentation that cancer cells need in order to function independent of appropriate oxygen levels. One study which has explored the glycolytic tendencies of cancer cells reports that cancer cells are observed to exhibit a metabolic shift from oxidative to elevated anaerobic glycolysis (Warburg effect). The effect is correlated with the increased gene expression of sugar transporters and glycolytic enzymes induced by common cancer-specific genetic alterations (Kannagi, 2004). Oxygen deprivation re-constitutes cells in such a way that they become structurally equipped with the capacity to engage in the sort of glycolytic activity that invigorates and perpetuates cancer cells. Warburg’s association between oxygen levels and tumor growth and aggressiveness contains important implications for contemporary cancer treatment and management which will prove effective if a holistic approach is used.
An Exclusive Article for Members
From THE BRIDGE Newsletter of OIRF
Published September 2008
Redaction by: Carolyn L. Winsor
© Copyright 2008, Dr. Karim Dhanani, ON Canada