Cancer as a Metabolic Disease

4/01/2012 5:33PM

Cancer as a Metabolic Disease(Review),
Thomas N. Seyfried, Laura M. Shelton
Nutrition & Metabolism, 2010, 7:7
Download the full paper here.

Abstract
Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.

It is nice to know that at my age I can still perceive my stupidity. This review paper reminded of concepts and findings in relation to cancer that I had long ago read about but only as an interesting footnote. I haven't studied cancer, except to say that I read enough of it to know that it is a terribly difficult phenomena to understand and I'd rather conquer a galaxy cluster or two than waste my time reading anymore about it because that would constitute a larger waste of time. I like aiming high and MOO3 sucks so I'll read something, if only because over the last 6 months I have read findings that raise serious questions about cancer being a disease of the genome.




Conventional medicine is dominated by the genome model, alternative medicine leans more towards the Metabolic model. Neither perspective can offer easy answers and while I despise the snake oil tactics of some in both fields I am equally concerned by the reality that conventional medicine cancer treatments are predicated on being able to make a buck out of it. That is not a bad thing but becomes a dangerous thing when it leads to the neglect of treatment modalities that may proffer therapeutic potential equal too if not greater than those currently being emphasised by conventional medicine. Even in my ignorance I know there is a huge amount of research addressing the anti-cancer potential of ginseng species, cannabinoids, DCA, and perhaps even some zeolite compounds, which are used as adjuncts in some conventional cancer treatments. Yet these are all natural compounds, you can't make a buck out of ém. We need Big Pharma but we also need much more diversity than that culture can provide. The current emphasis on "receptor interception" very much reflects the technological emphasis on designer molecules. To a man with a hammer! Very useful stuff but will  never be sufficient.

At the end of this paper the authors argue strongly for a severe caloric restriction as a means of defeating cancers. That is logical but not necessarily right. It is good advice and worth a shot but cancers are so adaptive and so heterogeneous magic bullets remain a long shot. An important caveat here:

Once you have learnt enough of this literature it becomes a little too easy to construct plausible explanations for what is going on. These are only stories and are a necessary part of the relevant cognitive processes but we must remember that until those stories are more deeply investigated we only have stories. We need more than that.

I'm not being critical of the authors, they have presented a very plausible story for others to investigate. That is exactly as it should be. Do not forget the enormity of the challenge here. If, as I suspect, the concordance between the central concept of this paper, the hypothesis of Davies et al, and the concept of Lynn Marguilis, holds up to further scrutiny it means we are fighting approximately 3.5 billion years of evolutionary survival strategy. Consider that in relation to this comment by David Baltimore, one of the world's leading bioscientists:

"In my view," he said, "cancer is a problem that will be part of human life for a long time, if not forever ... and I expect that therapy will be slow to come. Even when new therapeutics schemes come, the plasticity of tumor cells will make it very difficult to effect total cures. For those who hope for rapid progress, this is clearly a pessimistic view." But, disturbed by his own pessimism, he concluded, "But results will come, and we, as a nation, must maintain our commitment t6o finding everything we can about the disease and to try in every way possible to prevent or cure it. There is, of course, the real possibility that my whole analysis is wrong and that there lie out there magic bullets that will make a huge impact on cancer mortality rates in a relatively short time. To have judged so completely wrong would give me great pleasure."
Ahead of the Curve: David Baltimore's Life in Science, Shane Grotty

This paper puts forward a good argument to counter Baltimore's pessimism because it argues that underlying nearly all cancers(germ line cancers are rare, approximately 5%) is a mitochondrial metabolic abnormality that not only precedes a cell becoming cancerous but is the primary driver in creating a cancerous cell. This at least raises the possibility of a magic bullet or two because it suggests that by targeting this dysfunction it may be possible to kill cancerous cells. Undoubtedly that can happen but I know it is no guarantee because a cancerous cell is already very well equipped to survive a wide range of insults and prevent death signal transduction. For example, cancer cells will generate "death signals" to initiate apoptosis(programmed cell death) but these molecules can be intercepted by heat shock proteins that will bind to the messengers and prevent entry into the nucleus. So even if one activates the mitochondria(and I dispute their claim that cancerous cell mitochondria produce no ATP) to initiate death signals there is no guarantee that strategy will work for every cancer cell. Many cancer cells, if not most, demonstrate Hypoxia Induction Factor transcription, this being a transcription factor that initiates heat shock protein production. Not sure why, the usual explanation is that the high oxidative state of cancerous cells, probably brought about by mitochondrial dysfunction and proton leakage, induces HIF translocation to the nucleus. That is consistent with the literature. It also allows me another story: the reason why some antioxidants work against cancers is because the reduction in oxidative load sufficiently collapses HIF and HSF translocation thereby diminishing death signal capture by heat shock proteins and allowing apoptosis to follow.

This review paper caught me by surprise because they put forward a plausible argument that cancer arises principally from "stressed but not killed" mitochondria. The phrase "stress but not killed" was coined by my former collaborator in relation to post traumatic brain injury and how surviving cells can be compromised in their function and can set off trains of deleterious events in relation to neural transmission, neural health, and immunological status, which can result in a variety of problems emerging many years down the track. Parkinson's Disease is an excellent example of this because mitochondrial dysfunction is strongly implicated in that pathology. A recent paper claims that a specific antioxidant mix - MitoQ - proved very promising in Alzheimer related animal experiments. The name says it all - antioxidants specifically targeting mitochondria. It is perhaps not well known that intrinsic physiological processes of mitochondria are estimated to produce over 90% of all oxidation events in the body, so if you're going to load up on antioxidants it is absolutely essential to focus on antioxidants that specifically target the oxidation events in mitochondria. For example, alpha lipoic acid, asparagus, eat it til your pee stinks. Seriously. It is now well established that pathologies like Alzheimers, Parkinson's, and Cancers are years in the making.

Years ago I was struck by the research of Prof Bruce Ames et al where they managed to substantially improve the cognitive function of aged mice by supplementing their diet with two of the most beneficial mitochondrial relevant nutrients available: alpha lipoic acid and acetyl l carnitine. The good professor must have been impressed himself because he went on to found Juvenon, a company that provides the supplement for human use. The results of those experiments were striking. It is obvious that providing mitochondrial support will  provide improved cellular health but the improvement in cognition was remarkable and highlights how critical mitochondria are not only in relation to cellular health but also cellular efficacy. In the work of Ames et al what is also notable is the improved mitochondrial internal structure that emerged after weeks of supplementation. As this review paper notes cancer cells often present abnormal mitochondrial physiology and this may precede the cell becoming cancerous.

Longevity studies also highlight the importance of mitochondrial function in aging processes. Caloric restriction is known to induce a number of intra-cellular events that are beneficial to mitochondrial function, from increasing autophagy to reducing oxidation events from the electron transport chain. There is even evidence that under caloric restriction mitochondria will fuse and hence become more efficient in their function. Additionally, the enhanced autophagy probably precipitates the engulfment of not so healthy mitochondria(mitophagy) thereby reducing the potential deleterious impact on the same on cellular function. By increasing autophagy caloric restriction will also enable the removal of lipofuscin, a cell aging marker of accumulated waste products, from mitochondria, thereby enhancing function. According to the hypothesis put forward in this paper, the available evidence is powerfully in favour of occasional fasting as a means of substantially reducing cancer incidence because these fasting stages, especially if all carbs and sugars are eliminated, and if the production of ketone bodies can be enhanced, not only improve mitochondrial function but represent a significant threat to cancerous and pre-cancerous cells.

Stay hungry occasinally, it even activates CREB 1, a very important transcription factor in neurons that plays a  major role in memory formation. The neuroscientist Mark P. Mattson once wrote an article: Starve me and watch my brain run. His point was that caloric restriction is good for brains, rat brains at least, I think it is nearly always bad for human brains on the go so when fasting don't think too much! Perhaps that is why there is a  history of fasting AND meditation. Religious ideas can be entertaining, sometimes they can even make sense.

One has to wonder if the obesity levels, together with inordinately high sugar consumption, is going to entail an marked spike in cancer incidence over the coming decades. At present the data is only pointing to an aging population as the reason for the increasing rate but it is too early yet, it will be at least another 10-20 years before the possible tumorigenetic potential of a a few generations being fat and sugar laden.

I am struck by the seemingly critical relevance of mitochondrial function in relation to health in general and pathology in particular. I don't yet know what to make of this but given the given the concept provided by Lynn Marguilis(recently deceased) regarding the origin of mitochondria I have this vague sense that I am missing something really important. Especially given that this review paper highlights mitochondrial dysfunction and this meshes quite nicely with a hypothesis put forward by a group of scientists led the physicist Alan Davies: that cancer is the re-activation of an ancient genome process. I'm not sure but I suspect the Lynn Marguilis hypothesis indicates that mitochondria gave rise to complex cells or arose around the same geologic time frame and the Alan Davies team is suggesting an ancient genome process that precedes that time period. If that is true it becomes very interesting because the central thrust of this paper is how mitochondrial dysfunction leads to genomic instability which paves the way for cancer. This instability may be abolishing regulatory processes and moves the the cell towards a more primitive phenotype which is primarily about consumption and reproduction. Look at single celled organisms, they just keep dividing til the food runs out. That is what cancers do.

I can't do justice to the full argument in this paper, if you're interested you can download the full paper at the above link. The concept of mitochondrial uncoupling is fascinating, as is the need for energy balance in cells, and they do present plausible arguments as to how mitochondrial dysfunction not only precedes cancers but is also the cause of genome instability and subsequent tumorigenesis. Their primary argument is that without taking into account the Warburg Effect it is impossible to understanding the aetiology of cancer. A good argument that is well presented. I don't know if it is true but my hunch is this paper represents a valuable perspective on tumorigenesis that is much more powerful than the gene centric model. Accessible and interesting paper.