Cancer Cell metabolism: Warburg and beyond

Recently an essay appeared in Cell on "Cancer Cell Metabolism: Warburg and Beyond". It tries to establish a framework for understanding on the altered metabolism of cancer cells.In 1920 Warburg found that even in presence of ample oxygen cancer cells metabolize sugar through glycolysis. Glycolysis is an anerobic process and is less efficient in producing ATP molecules than its aerobic metabolism counterpart.

Why it happens? Lets discuss in little more detail in simpler language. As an early tumor grows, it outgrows the diffusion limit that blood vessels can supply. Thus, it causes hypoxia(Oxygen deficiency) in the surrounding cells. Hypoxia leads to decreased dependency on aerobic respiration leading to glycolysis.

It has also been shown that prevention of glycolysis leads to attenuated tumor growth and possible reversal of tumor cells into normal cells. Inhibition of lactate dehydrogenase LDH A forces cancer cells to oxidative phosphorylation in order to reoxidize NADH and produce ATP (Shim et al., 1997
,Fantin et al., 2006
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Its also known that the altered biochemical pathways in tumor cells leads to changed programmed cell death(Apoptosis). Overexpression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) prevents caspase-independent cell death, presumably by stimulating glycolysis, increasing cellular ATP levels, and promoting autophagy (Colell et al., 2007). Whether or not GAPDH plays a physiological role in the regulation of cell death remains to be determined.

Although altered metabolism confers several advantages on the cancer cell, it does not come without disadvantages. As a consequence of a deranged or simply overactive metabolism, cancer cells may be burdened with toxic byproducts that require disposal. So far, there is relatively little evidence for this hypothesis in the existing literature, but a few examples do suggest that cancer cells require detoxification mechanisms to maintain survival. Although there are enzymes that detoxify exogenous toxins, several “house-cleaning” enzymes, a term coined from studies in bacteria, deal with endogenous toxic metabolites (reviewed in Galperin et al., 2006). The best example of “house-cleaning” enzymes are the NUDIX (noncanonical nucleoside diphosphate linked to some other moiety X) hydrolases, a family of enzymes that act on the nucleotide pool and remove noncanonical nucleoside triphosphates. When incorporated into the DNA, these aberrant nucleotides can lead to mismatches, mutations, and eventually cell death. The dUTP pyrophosphatase (DUT), which hydrolyzes dUTP to dUMP and prevents the incorporation of uracils into DNA, may play a role in resistance to thymidylate synthase inhibitors. Suppression of DUT sensitizes some cancer cells to pyrimidine antimetabolites, suggesting that inhibition of these cellular house-cleaning enzymes may be an effective adjunct chemotherapeutic strategy (Koehler et al., 2004).

The lactate production associated with the shift to a glycolytic metabolism is thought to contribute to the acidification of the microenvironment. Able to adapt to and even benefit from an acidic environment, cancer cells have been shown to upregulate vacuolar H+-ATPases, Na+-H+ antiporters, and H+-linked monocarboxylate transporters (reviewed in Gatenby et al., 2004). Inhibition of these adaptive mechanisms can lead to decreased viability of cancer cells and increased sensitivity to chemotherapeutic agents (reviewed in Fais et al., 2007, Fang et al., 2006).

Many mysteries remain unsolved in our understanding of even normal human metabolism, let alone that of cancer cells. The metabolic pathways of the mammalian cell and their many interconnections are incomplete, as many enzymes remain unannotated in the human genome. Although we have guesses by homology, the identities of the human enzymes that catalyze reactions we know must occur are still elusive. In addition to annotating all human metabolic genes, the “ins” and the “outs” (i.e., the metabolites that enter and exit cells) should be measured and cataloged. It is also entirely unclear what percentage of the cellular fuel is normally used for ATP generation, biosynthesis, or other processes. And with few exceptions surprisingly little is known about intercellular metabolism. Much of our understanding of metabolism has been inherited from work in simple organisms; the compartmental nature of human metabolism is an exciting area of potential exploration.

Although aerobic glycolysis is the most characterized, although still puzzling, metabolic phenomenon in cancer, many other aspects of cancer metabolism are likely to be derangements of normal metabolism and ought to be elucidated. The nutrient conditions of the tumor microenvironment have not yet been carefully examined. Cancer cells, despite engaging in energy-costly processes, must still be able to maintain ATP levels, by either relying on increased flux through glycolysis or utilizing a diversity of fuel sources. Several hypotheses exist as to why a fraction of tumors are refractory to imaging by FDG-PET. One possibility is that certain cancer cells may not be primarily glucose-metabolizers but may rely on alternative fuel sources, the detailed characterization of which may lead to the detection and treatment of “PET-negative” tumors. Furthermore, there are more complex questions to be answered: Is it possible that cancer cells exhibit “metabolite addiction”? Are there unique cancer-specific metabolic pathways, or combinations of pathways, utilized by the cancer cell but not by normal cells? Are different stages of metabolic adaptations required for the cancer cell to progress from the primary tumor stage to invasion to metastasis? How malleable is cancer metabolism?

From a therapeutic perspective, knowledge of the causes, benefits, and vulnerabilities of cancer cell metabolism will enable the identification of new drug targets and will facilitate the design of metabolite mimetics that are uniquely taken up by cancer cells or converted into the active form by enzymes upregulated in tumors. Profiling of either metabolites or enzymatic activities may allow us to develop diagnostic tests of cancer, and metabolite derivatives can be used for the molecular imaging of cancer, as exemplified by FDG-PET. We find the possibility of a new class of cancer therapeutics and diagnostic tools especially exciting. Therefore, we emphasize the need to explore beyond a glucose and energy-centric driven model of cancer metabolism to a broader one that encompasses all of the metabolic needs of a cancer cell. Perhaps it is time to step out from under Warburg's shadow.