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Mainstream Science's Dogma Reversal: Aerobic Glycolysis/ Metabolic Alterations are finally seen as Necessary for Cancer Cell Initiation/ Maintena

Mainstream Science's Dogma Reversal: Aerobic Glycolysis/ Metabolic Alterations are finally seen as Necessary for Cancer Cell Initiation/ Maintenance.

Gregory S. Bambeck Ph.D. and Michael Wolfson J. D., M.B.A 

Summary

          After a half of a century, mainstream big science has completely reversed its dogma on how it is necessary that cancer cells partition their nutrient resources, in a specific way, between material for cell growth and energy production. A thirty years ago modified version of the originally rejected Warburg theory, now has powerful support from newly integrated metabolic pathway studies and core system therapies. This theory was worse than ignored, as it was actively squelched by a small, but elite group, controlling the publication and funding philosophy of cancer during this whole time span. Only the future will tell how much human suffering, could have been prevented, if just honest inquiry and scrutiny had also been allowed to flower, instead of the exclusionary and prejudicial pursuit of personal influence over pet investigative paradigms. Much precious time, knowledge and human life were lost enforcing such preconception, assumption, and opinion upon the course of scientific investigation. Fortunately, but belatedly, data and fact finally triumphed over politics and elevated position. Newly discovered metabolic control systems may benefit us all, not only in the medical area of cancer, but in therapeutic arenas of some other major diseases of aging, as well. A brief human, scientific, data and fact history is contained, herein.

Introduction

          In a watershed reversal of an entrenched fifty four year old dogma, Science magazine published a Special Section issue on 12/03/10 devoted to metabolic energetics; and more so to the diseases of aging, such as heart disease, diabetes II and especially, cancer. Most important, from a historical (and this document's) standpoint, is the article on p.1340 by Levine and Puzio-Kuter, which concludes that key elements of the Warburg aerobic glycolysis hypothesis are critical to and necessary for the initiation and maintenance of the transition from the normal cell to cancer cell metabolic pattern. In most of our previous (and this) papers, we refer to this conversion as the cancer ‘metabotype.' This publication did not surprise us, as our prediction that such a ‘revelation' would happen soon, has its basis not just in new, but in firm, and very old, evidence. From 1956 to near present times, such a pronouncement would have been considered heretical, and so taboo as to be refused publication in any major scientific journal or to have received any research funding by any respectable granting agency. This sorry story goes back to the mid twentieth century. Although science itself may be impartial, scientists, being all too human, are not. Their organizations and institutions consist of hierarchies of power, influence and opinion no different from that of any other political system. Sometimes, even the ‘show me', ‘replicate to prove', and peer review crosscheck and verification safeguards of scientific inquiry can be swept away in the emotional heat of the moment. As such, was the fury and wholesale rejection surrounding the towering influence of the Nobel laureate, Otto Warburg and his aerobic glycolysis hypothesis. Fortunately, for science and the rest of us, blunders of this magnitude are rare.

     Science, for all its outward appearances of rational intelligence and progresses that have arisen from its aggregate achievements, can obscure the view from inside individual laboratories or in narrow areas of specialization, where it can be actually shown that science moves forward more so in fits and starts, lurches and bounds and often in haphazard random walks. Scientific disagreements usually take place without much beyond a few political ripples, as friendly (or otherwise) combatants ruffle each other's feathers on a one to one, or small group basis. In short, things do not normally get out of hand.

     Such is not the case with the Warburg  hypothesis, or the refinements of its one and only significant shortcoming. For over a half of a century, the subject of aerobic glycolysis has been verboten; sealed with skull and crossbones. In 1956, Warburg's two valid hypotheses went down the same drain used to flush down his third imperfect hypothesis. More significantly, even the study of general intermediary metabolism, itself, has moved into similar backwaters for the last 30 years. How and why did this happen? What has caused such a profound reversal in our thinking? How have we, (science and medicine) been hurt by this?  Can we, or do we resolve the inequities of the past and/or give credit where credit is due? What are the medical implications of our newly found logical reversal? Where do we go from here?

          Answers to some of these questions, in part or more fully, are available in the Science article referenced in the second sentence of this paper. We highly recommend that the reader look into this article, because it (ever so quietly) represents probably the biggest biomedical upheaval, reversal and revolution in more than a half century. This is no small potatoes. We are looking at a genuine historical paradigm shift of momentous dimensions, the historical importance, of which, aerobic glycolysis naysayers would wish to remain hidden in the attic, like a senile grandparent, because the ‘unquiet' story version is simply just too embarrassing. We know this is true, because one of us was there; lived it. We take a little different tack than Science, when answering such questions and while remembering the fifty-four year aformentioned history. We are going to talk a little science, but the real heavy stuff we will leave to the reader to find in our short, but highly informative reference list. Regardless, it helps to have a basic background in metabolics, nutrition and bioenergetics or biochemistry 101. For the less technically initiated, scan over the science stuff, paying deeper attention to the human narrative woven throughout this document, as it is instructive in its own way.

 Ancient history: Warburg and Aerobic Respiration   

     About 70 years ago, Otto Warburg, a highly prestigious paragon of theoretical metabolics, hypothesized that aerobic glycolysis, lactic acid production and mitochondrial respiratory deficiency were a triple requirement for the conversion from a normal to a cancer cell. This cellular state completely changed the way a cell made the vital energy carrier molecule, ATP, which is required to power most cellular functions. In a normal cell, glucose is the primary fuel burned to make ATP. This occurs in two stages. The first stage, called glycolysis, burns without oxygen, produces two ATP and feeds its product, pyruvate, into the second stage, called the Kreb's-OX/PHOS system, which burns with oxygen and produces 32 ATP. The second system also makes two ATP without oxygen. Thus, in total, four ATP (12%) result from burning without oxygen (substrate phosphorylation) and 32 ATP (88%) are made by burning to carbon dioxide, with oxygen (oxidative phosphorylation-OX/PHOS). Glycolysis occurs in the cell cytoplasm, while Kreb's-OX/PHOS occurs in the cellular organelles called the mitochondria. When oxygen concentrations are limiting (hypoxia), mitochondria cannot burn all the pyruvate that glycolysis produces. So instead, the pyruvate, is converted to lactate and exported from the cell. Rather than dying an energy death due to lack of ATP, the cell elevates glucose importation and the rate of glycolysis increases dramatically (often exceeding 1000%) to make up for the ATP energy production shortfall. When oxygen levels rise, the normal cell system returns back to its efficient 12/88% ATP production ratio. This we call the Pasteur affect. This return to normal does not occur in cancer cells when adequate oxygen supply returns to normal, once again. Thus, Warburg used the term aerobic glycolysis, when ascribing this phenomenon to cancer cells. Warburg stated that cancer cells were different from normal cells in that they were ‘stuck' in a state of 1) elevated glycolysis, 2) elevated lactate production and 3) mitochondrial oxygen consumption deficiency.  

          It was postulate number three that became the fly in the ointment. Scientists successfully attacked his mitochondrial respiratory defect concept because many cancer cell mitochondria had normal respiration. Warburg countered that low mitochondrial numbers, on a per cell basis, could yield the results seen, as it is the cell, which is the unit of life. This whole debate came to a head in 1956-1959, in a duel between Warburg  and Weinhouse, Chance and others. Warburg's third hypothesis was upended, when it was demonstrated that more than just a few types of cancer cell mitochondria have normal respiratory chains and that a small number of cancers even show elevated respiration on a ‘per cell' basis (Warburg, Science 123, 309-314, 1956. Weinhouse, 124, 267-269, 1956. Chance, 128, 700-708, 1959). When Warburg shifted his emphasis toward mitochondrial ATP production deficiency, Weinhouse countered by assuming that normal carbon dioxide production and oxygen consumption were a proof of adequate ATP production. Weinhouse was wrong on this one, but it was before the days of the chemiosmotic hypothesis of Mitchell, and the concept of respiration being uncoupled from ATP was unknown and not readily measurable with the technology of the times, so his knowledge error can be overlooked, but his assumption cannot, because it was no more proven than its antithesis. Even though Weinhouse was very wrong, he won the day. In fact, he won the next four decades, and even in 1999, metabolism was still not considered in Hanahan and Weinberg's highly touted ‘six hallmarks of cancer', even though by this time, convincing data to the contrary had been available for more than 25 years. By this time, not only was such thinking wrong, but it was ‘wrong on steroids, wrong' as they say, these days, and as we shall show, later. Suffice it to say, that Warburg was dethroned, and like fallen rock stars, giants of science rarely arise again to any degree of former glory. Moving his target from oxygen to the cell to ATP undid him.

          From that time forward, cancer cell metabolism, and bioenergetic metabolism became the handmaidens of regulatory molecular biology. By the 1970's, genomic instability, mutability, oncoviruses, signaling systems, immortalization, growth factors, growth factor suppressors, angiogenesis, metastatic cell recognition etc. became the research paradigm focus of cancer causation, while aerobic glycolysis was perceived as a mere effect of these ‘greater' factors. By the time the 1980's rolled around, genomics, followed by massive DNA sequencing and mining in the 1990's, completely dominated the cancer research agenda, to the point that their was no one left who could even remember thinking of cancer in metabolic terms. Below, we tell a brief story about someone who did think about it, and deeply.

Intermediate History: A Single Case Study

     About 20 years after the 1956 Warburg debacle, a young and very politically naïve Kent State University graduate student thought that he saw something that caused him to revisit the Warburg hypothesis. In short, he agreed that respiratory deficiency, on a per cell basis, was not a feature of all cancer cells, but was common to many tumor types, but also, that something was ‘funky' about cancer cell mitochondrial ATP production.

     A new semi-micro-technique had arrived in the early 1960's that allowed us to measure the actual number of ATP produced per oxygen consumed in isolated mitochondria, which could measure to what degree ATP production was actually linked (coupled) to oxygen consumption. In general, and without getting into details, mitochondria produce three ATP per oxygen consumed when 100% coupled. Anything less is considered ‘uncoupled,' and is expressed as a ratio of full coupling in terms of the ADP/O ratio; i.e. an ADP/O of two tells us that mitochondria are 67% coupled, or 33% uncoupled, as one might prefer it. Thus, uncoupled mitochondria are measurably ATP production deficient. Since our grad student only had a single mouse lymphoblastic lymphoma model in his own lab, he decided to review and compile, and conduct a broader experiment as an armchair exercise, by reviewing the literature, which was subject impoverished, but adequate. We call this gedanken, or mind science, often employed by pure theoreticians.

          What he did find was that per cancer cell mitochondrial ATP production, was severely diminished in all cancer types in which there were mitochondrial population, respiration and/or ADP/O data. He concluded that virtually all cancer cells might have lower than normal Kreb's-OX/PHOS produced ATP as a result of 1) lower than normal numbers of mitochondria per cell, 2) deficient respiration per mitochondria, 3) decreased Kreb's cycle/NADH production, 4) lowered coupling to OX/PHOS or 5) a combination of any two or more of the above. Whether the per cell mitochondrial ATP production shortfall was due to an intrinsic internal central system defect(s) in the actual mitochondrion itself or whether it was due to some external regulatory control element(s) defect(s) did not matter, as long as the net output ATP deficiency was the same end result. "By whatever means," "must be present" and "on a per cell basis" was the central mantra of his dissertation: Mitochondrial Alterations in a Lymphoblastic Lymphoma Transplanted into DBA/1J Mice. He also showed how this necessary aerobic glycolytic change would switch the whole of the panoply of intermediary metabolism into state of relentless cell growth, as a cause of cancer, and not an effect. As we shall see, thirty years later, we finally know all of these propositions to be true.

          This kid was not only naïve he was a glutton for punishment. Among other things, he was an intermediary metabolism junkie. He memorized every chemical structure and reaction of the thousand plus biochemical components of the intermediary metabolic system and stared for endless hours, (for over three years) at the accumulated metabolic pathway charts that covered the entire expanse of his bedroom walls. In time, the charts began to morph from a gigantic hairball of nouns into the dynamic singularity of a verb. It became clear to him that mitochondrial Kreb's-OX/PHOS ATP production deficiency, in the presence of glycolytic enhancement and pyruvate diversion to lactate, would shift the whole schematic toward anabolism in exactly the way necessary to enforce irreversible cell growth, and to satisfy ATP requirements.

          As a for instance, in the presence of dramatically enhanced glucose importation, elevated glycolytic fetal enzymes, pyruvate diversion and Kreb's-OX/PHOS deficiency, a number of things must, and do, happen. Glucose becomes partitioned between glycolysis and the pentose phosphate shunt (PPP), an anabolic drive system, which can be assisted by a pyruvate log jam that piles up glycolytic intermediates, principal, of which, is glyceraldehyde-3phosphate (G3P). Glucose and G3P are feedstocks for PPP. The PPP canon taught is that the PPP principally provides NADPH for anabolic reduction, and ribose for nucleotide synthesis. A lesser emphasized hat trick of PPP is that it generates its own feed stocks, glucose phosphate and G3P, as its outputs, thus reinforcing its own pathway inputs to deplete glucose to carbon dioxide, via anaerobic hydrolysis. Also little regarded, but worthy of honorable mention, is that the phosphorylated PPP feed stocks, do not burn up all the ATP energy in their formation, but conserve some of it as high energy intermediates. This is also true of NADPH, which defuses highly mutagenic reactive oxygen species (ROS) from systems like uncoupled OX/PHOS.

          Our grad student also envisioned Kreb's-OX/PHOS ATP production inefficient mitochondria as participating in the anabolic process via its amino acid transaminases and amino acid exchange shuttle systems, in concert with the urea cycle ornithine decarboxylase (ODC) off ramp to help provide a balanced nitrogen substrate mix for protein and nucleotide synthesis. The ODC pathway participated in tumor metabolism, as ODC blockers can inhibit cell growth and induce differentiation in some cancers. He did not view the mitochondrial glutamine pathway as a glycolytic substrate phosphorylation and ATP generation synergizer or partial glycolytic alternative in cancers that were not rampantly glycolytic. He saw it as included in the nitrogen balance amino acid system. Yes, it is also true that alternative glutamine pathway upregulation can make an aerobic glycolysis contribution in some tumors, but it does not seem to be a ‘metabotype' necessity, as it appears to be, most often, an adjunct that assists aerobic glycolytic substrate phosphorylation in exacerbating the cancer metabolic phenotype, and is not significantly present in many cases. Regardless, its substrate phosphoryation ATP contribution is substantial and supports glycolytic up regulation in some cancers. Not surprisingly, he presented his case with condensed metabolic flow diagrams.

          Although there was virtually no research on the topic at that time, our grad student was heartened to find that Kim and Song, in 1976 and 1978, had seen incredible cancer cell kill rates with 5-thio-D-glucose (5TG), a glycolytic inhibitor. This indicated that their tumor model cancer cell mitochondria could not recover for the lost glycolytic cellular ATP production from such an insult, while normal cells were unaffected. In fact, in vitro, 99.9999% of their cancer cells died, in four hours, with 5TG and radiation while normal cells lived, and were actually radiation protected! This shows the potential of a direct aerobic glycolytic pathway attack synergy with conventional therapy. Imagine how far we could have run with a ‘concept' ball like this by now, if we had only taken advantage of the 32 years ago head start, instead of having to ‘rediscover' other glycolytic blocking agents in just the last few years.

          With his ‘unassailable' armaments in hand, our intrepid graduate student went to cell biology and physiology meetings for several years, only being allowed lowly poster sessions because their were no symposia on the subject and no podium presentation space available for such topics. One would think that such a global hypothesis, with ancient debate resolving data and such stupendous differential cancer cell death rates, at least, would inspire debate. Among the young scientists, there was no debate because they had no idea what the H he was talking about, most of them, never even having heard of the Warburg effect. Among the old guard, there was no debate because they dismissed him out of hand, derided him or flat out abused him. It was worse than humiliating that there was not even enough consideration for rational discussion. The chronic "We don't believe that crap anymore." type of response, was more like a religious rejoinder than a scientific argument. His vague hopes of publication, at least as an ‘off the wall' and ‘crazy', but a somewhat creative and forward thinker, evaporated, when rejected, even by the ‘liberal' Journal of Theoretical Biology. Having been (un?)duly castigated by the reigning Olympic gods of science, he assumed the appropriate ‘insignificant insect' posture and opted to publish his dissertation under the aformentioned more humble title, as opposed to the more strident version appearing after the colon in the title of this present article. Oh! Incidentally, his lymphoblastic lymphoma mitochondria were completely uncoupled, in direct opposition to the full coupling of all normal tissues tested.

     So, here we sit, thirty much too many years later, ‘rediscovering' a brand new discovery! killing cancer through taking advantage of its ‘sweet tooth'. Not only had they thrown out the baby with the bathwater, and then the tub and the plumbing fixtures; now, they have even ‘discovered' this whole, new thing! called a bathroom. Meanwhile, all this happens while a special edition of Science decries the paucity of existing intermediary metabolic specialists because the field is now so unbelievably fallow. Go figure.

          So, what has become of our ‘insignificant insect'? He remains as unknown today as he was thirty years ago, in spite of the fact that his postulates outlined a simple and direct, but adequately detailed description of the central metabolic and energetic framework (sans glutamine, partial oops!) that we now know to be true. However, he finally has a sense of belated relief, now that a critical area of cancer research is receiving its due scrutiny. Scrutiny was no more than what he was asking for, in 1980, in the first place.

          Following 1980, molecular biology entered the age of genomics, with DNA fingerprinting, DNA sequencing, gene splicing and cloning, leading the pack. By 1990, this had taken on all the trappings of a genuine gold rush. The DNA molecule became the new belle of the ball of life science, while protein function, now called proteomics, became a wallflower. That is, by no means, a bad thing (except for the proteomics part). A new and bountiful harvest of knowledge, unlike anything ever seen in the life sciences, was being born. The DNA light of new understanding was burning so brightly as to ‘blind, shock and awe'. Although hidden in the data storm, eventual salvation for aerobic glycolysis was grinding slowly, but relentlessly, through the back door.

          However, this would still take time. For the next two decades of the 80's and 90's, cancer cell metabolism investigation, now reduced to a sub-handmaiden to genomics, and already reeling from its first two decades of insult, was now in line for 20 more years of the same. Even as late as 1999, Hanahan and Weinberg did not even mention metabolism in their famous six hallmarks of cancer, those being: 1) growth signal self activation, 2) growth suppressor  inhibition, 3) programmed cell suicide evasion (anti-apoptosis), 4) immortalization, 5) sustained vascularization (angiogenesis) and 6) metastatic tissue invasion. These may have sounded complete at the time, but it had been a long cold winter for cancer metabolism, and things were about to change.

      After the human genome project finished at the turn of the century, the scientific community woke up to an obvious next question. We have over 22,000 genes here, coding for proteins, the functions of the majority of which, we are clueless. What do the proteins that all these genes code for, actually do? After the turn of the millennium, this question would lead us back, full circle, to a real serious and sober rethink of a modified Warburg hypothesis. As unsympathetic as it may sound, it helps that the old school knee jerk anti-Warburgians are now  mostly gone, and aren't around to manipulate, ‘bulldog' and run roughshod over contrary thought. In addition, a dearth of metabotypic data has permitted a new crop of open-minded scientists to arrive with unencumbered metabolic preconceptions onto a fresh playing field. What a new playing field it is! There now exists a profusion of data around cancer cell intermediary metabolic regulatory control systems that would have had any graduate student from thirty years ago brimming in anticipation of understanding their significance. Some of this meaning is just coming into the light, like a fresh marriage between then and now, reminding us of the phrase; "Something old, something new, something borrowed, something blue." 

Present History: The New Millennium

     During the last decade, since the turn of the millennium, the golden age of biology went from a promise to a reality. Not only has there been a zillion fold increase in the speed of molecular, genomic and proteomic data collection, but there has also been a similar concomitant decrease in the price per data point collected. For example, in the last ten years, DNA sequencing has decreased its time/price ratio from 5 years and $3 billion per genome to 3days and $10,000 per genome. This represents a 99.6% improvement in time and a 99.996% reduction in price that yields a 99.9999%+ overall improvement in efficiency. This comes with a promise of a 100 times more efficiency increase over the next couple of years. Similarly, computational speed, memory and topic specific software have kept abreast with the barrage of genoproteomic and metabogenoproteomic information, and most noticeably, on a gene conservation evolutionary scale. In the case in point, that being, our cancer metabolism discussion, a much deeper understanding of the huge and growing array of metabolic control elements has led us to a more mechanistic understanding that a modified Warburg hypothesis is correct, and may provide us with, paradoxically, a smaller, but more powerful suite of  differential cancer cell killing strategies and molecules. There is also evidence (from now and thirty years ago, as the reader may recall 5TG) that these central pathway target molecules could synergize with lower dose forms of existing chemotherapies that could confer fewer and milder side affects, and that they could dovetail with simple dietary and life-style changes.   

          In this brief review, we will be providing a kind of ‘Cliff Notes' rendition of the regulatory control metabotype system, as we now understand it, because its interaction set is huge. Otherwise, this article would become a more burdensome tome than it already is. Instead, we will later provide about a handful of Wow! Gee-Whiz!  BIG SCIENCE review articles, so that you do not have to wade through a lot of the professional ‘muck' to get to the real juice. Besides, their bibliographies provide all the ‘muck' that you would ever need. However, we believe that it is very beautiful muck, so, have at it.

           Shortly after the year 2000, the nutrient and energy sensing regulatory metabolism control papers began to grow, and then expand profoundly around 2005. Almost immediately thereafter, some of the regulatory pathways came into focus, and soon, the dam burst wide open. By the latter part of the decade, we understood that an interwoven and layered regulatory hierarchy, was integrating the primary glycolytic and mitochondrial intermediary metabolic pathways in all dividing cells, be they embryonic, wound healing, adult replacement or cancer cells. The only caveat was that cancer cells were mutationally ‘stuck' in this metabolic trench while normal cells were not. This was a genuine new discovery in that it demonstrated a new level of aerobic glycolysis creation, control and dynamics. This is a higher level of manipulation of the same core system described in 1980. This rendered the cancer ‘metabotype' to be true. Thus, central aerobic glycolysis blockers, and blockers of their regulatory pathways should inhibit or kill cancer, which is also true. The new notion is; that if we could identify the specifics of the system more rationally, and with a more diversified weapon set, we could do some serious damage to this disease we call cancer. The system is so anciently conserved in evolution that system modifiers should be strewn (like resveratrol, anti-oxidants etc.) throughout the world's ecological biota. Some new weapons are already emerging and the beneficial results tell us that there is a lot of work yet to do, but with a plan. The good news is that we finally know where we are going. If there was ever a time for the pharmaceutical companies to stand tall, this is that time. If there was ever a time to throw a buck at cancer research, this is that time. Using cancer's own growth system against itself would be preferable to the historical strategy of beating it to death with primitive chemical and radiation clubs that also kill normal cells and render the patients ‘sicker than dogs.' Thus, this article also registers a vote for the importance of the preservation of the world's ecosystems.

      New core pathway blockers are already showing some promise. For instance, 3-bromopyruvate (3BP) blocks Hexokinase II, a mitochondrial ATP highjacker, that dramatically enhances the glycolytic and PPP systems. This resulted in total eradication of 100% of metastatic tumors in rats, in a hepatocarcinoma model system. Similarly, dichloroacetic acid (DCA) inhibits pyruvate kinase-2 (PKM2), a fetal pyruvate to mitochondria blocker found in a broad range of tumors. Purportedly, both 3BP and DCA kill cancers that cannot up regulate mitochondrial OX/PHOS due to critical central or regulatory pathway mutation, while shrinking or halting growth in benign and metastatic cancers that can still maintain enough OX/PHOS for quiescent survival. Although both are preferable to the full blown disease, cancer kill is preferable to growth stoppage, because it eradicates the tumor, while growth arrest is more akin to resetting the clock on a time bomb, as an already mutated system simply awaits not much further mutation, which may or may not happen. But, hey folks! At this point, we will take any port in a storm. DCA is yielding results in a broad array of animal cancers, and clinical trials are underway in human brain glioblastomas. Preliminary results are not short of thrilling. We already discussed 5TG, as something old. Other aerobic glycolysis and mitochondrial blockers are in the works, as something new.

     In addition to the core, or central metabolic pathways of aerobic glycolysis, an interwoven and layered set of regulatory pathways control the central pathways. Genetic errors in the regulatory pathways can force the central pathways to get ‘stuck' in the cancer metabotype. Blockers, rectifiers and mutations in these pathways institute the same or similar effects as seen by blockers, rectifiers and mutations in the central pathways. For example, when driven by mutated nutrient sensing growth signals or repressed by activated mutant energy sensing growth suppressor signals, aerobic glycolysis is instituted, and multiple benign tumors result, in animal models. Eventually, these new highly ROS enhanced, and therefore, mutagenic tumors, go metastatic. Throwing a monkey wrench into this aerobic glycolysis activated system can kill the cancer, but spares normal cells, because they are adaptable.

     If there is anything approaching a metabolic main control element in the nutrient fuel and energy sensing metabolic regulatory system, it is target of rapamycin (TOR). An actvated TOR switches the system toward nutrient importation, OX/PHOS inefficient anabolism and cell growth, while an inhibited TOR switches the system toward internal metabolite recycling, OX/PHOS efficient catabolism and cell quiescence. Like a spider in the center of a web, with all legs tuned to a host of quivering silk strands, TOR performs a balancing act between the parts of a huge array of individual inputs from an integrated ‘cross-talking' set of metabolic status sensors. Then, it activates and represses, in turn, gene activators and repressors of several thousand genes that change metabolism, which in turn, changes the inputs from its metabolic status sensors. This regulatory feedback system allows the cell to settle into several principle types of homeostatic drive states such as cell growth and division, quiescence, response to starvation, ROS load and cell component stress damage. The elucidation of the regulatory TOR affected and effected systems are what finally cemented the modified Warburg concepts into stone.

     Briefly, the cell growth factor nutrient sensing IGF/P13K/AkT/TOR pathway upregulates HIF to stimulate anaerobic glycolysis and PGC-1alpha to institute mitochondrial neogenesis, which makes new, but OX/PHOS inefficient mitochondria. This activated TOR pathway inhibits the 4B-EP mitochondria regenesis pathway, which when stimulated, up regulates respiratory gene activation, in turn, rendering mitochondria OX/PHOS efficient. These are pro-cancer and anti-cancer systems, respectively, as well as being pro and anti-metabotype. We use the terms neogenesis and regenesis to distinguish between the two separate phases of mitochondrial biogenesis. When operating normally, the cell growth system institutes a temporary and reversible pseudo-aerobic glycolysis, and when mutated, this process gets irreversibly ‘stuck,' and institutes the cancer metabotype. In addition to up regulation of glycolysis, HIF activates vascular endothelial growth factor (VEGF), which institutes angiogenesis. Thus, we now know that three of Hanahan and Weinberg's six hallmarks of cancer form a singular direct TOR systems link to aerobic glycolysis. The fact that the immortalizing ribonucleoprotein, telomerase, relocates from the mitochondria to the nucleus under this metabolic condition, as it does in rapidly dividing embryonic cells, implicates a fourth hallmark. The fact that the activated TOR system also turns off autophagy and down regulates the apoptotic cell suicide program, in addition to the notion that growth rate progression and metastatic invasion typically correlate with a progressively more ruthless aerobic glycolysis drive state, as adjuncts to the last two hallmarks, cannot be overlooked. In spite of the thousands of mutated oncophenotypes that plague our present cancer cell miasma, the modified Warburg effect remains the most central, consistent, and universal ‘hallmark' of pre-cancerous hyperplasia, cancer cell initiation, cancer cell maintenance and cancer cell progression that we know of. Maybe, we need fewer hallmarks and less assumption. Now, Weinhouse and Weinberg are both wrong. The ‘Wein' philosophy followers should, by now, be retreating from their dogma.

     Even with a virtual absence of knowledge of the external regulatory interactions between Kreb's-OX/PHOS and glycolysis, in 1980, the system, at that time, was conceivable from its central elements alone. This was possible for our grad student, because it is the central system that is changed, regardless of whether it is driven by core internal defects or external regulatory pathway defects. The bifurcation of mitochondrial biogenesis into growth driven Kreb's-OX/PHOS inefficient neogenesis and Kreb's-OX/PHOS efficient regenesis is real illuminating, particularly in helping to understand more esoteric regulatory features than those provided in the 1980 hypothesis.   

     For those who wish to delve ‘knee deep' into this system, a general overview, with simple life style practical applications, is available in our article: Cardiovascular Disease, Cancer cell Metabolism, Diabetes II, Muscular Wasting and Life Extension are all Linked as a Single Controllable Molecular Pathway, by Bambeck and Wolfson, which can be search engined on the internet. For those who wish to plunge ‘eyeball deep' into these systems, they can look up the following articles: (Z. Feng, Cold Springs Harbor Laboratory Press, 2010 p.199; I. Topisirovic and N. Sonenberg, Science, 327, 3/5/10 p.321; L. Fontana et.al., Science, 328, 4/16/10, p.1223; T. Seyfried and L.Sheldon, Nutrition and Metabolism, 7,7, 1/27/10; and for multiple papers and articles, Science, Special Section, 3/12/10, p.1337). Search engine word sets like AMPK-TOR-cancer; mitochondrial regenesis or neogenesis; Bambeck-cancer and/or life extension; caloric restriction pathway; aerobic glycolysis-Warburg and other obvious search engine words in this article will get you to anywhere you want to go.

     The main reason that there is such a recent explosion of work on the nutrient sensing IGF/P13K/AkT/TORc1/HIF and its converse energy and stress sensing p53/AMPK/TORc2/ROS/FOXO/SESN loop pathways has to do with the fact that they cast such a broad net. First, they are highly conserved in the evolutionary tree, from yeast to humans. Second, they integrate across a wide array of disease vs. health, conditions. The cancer metabotype is just the tip of this iceberg, albeit being one damn big tip; big enough for it to be a mega-topic all its own. The relative ease and simplicity of controlled manipulation of the core and regulatory elements of this system promise to deliver a powerful anti-cancer armamentarium, in addition to providing  weapons and life style tools for fighting heart disease, muscular wasting, obesity and diabetes II. Including cancer, these diseases/conditions are often referred to as ‘the diseases of aging,' and account for a whopping 85% of all death in the developing and developed world. Probably the most surprising discovery of all is that up regulation of the AMPK/TOR/SESN loop initiates genuine life extension beyond the normal maximum via caloric restriction (CR). Even more astounding is that CR mimetics such as metformin (an AMPK activator and anti-diabetes II drug), rapamycin (a TOR inhibitor and anti-tissue rejection factor) and perhaps, ‘high bioavailability' resveratrol (a common dietary supplement, AMPK activator and anti-oxidant), fight all of these major diseases. They reduce diabetes severity via increased insulin sensitivity, inhibit cancer cell metabotype formation as previously described, promote weight loss via lipid catabolism up regulation, decrease muscular wasting and cardiac insufficiency via mitochondrial regenesis and extend life beyond its normal maximum length via increased cell cleaning autophagy, ROS reduction and all of the above items described. We talk in more detail about the life extension pathway in our aforementioned publication.

     These diseases already strain our national budget to the breaking point, and threaten to undermine and overwhelm our economy in the next decade or two. With our present economy spending almost a fifth of its GDP on medicine, we have never been in more need of the proverbial white knight in shining armor. Well folks, this just might be that white knight, albeit a rather historically beaten, bruised, tarnished, but finally renewed and reinvigorated white knight. If we are lucky and if we are right, all we need to do is roll up our sleeves, get to work, and send cancer back to the same hellhole where it came from. Maybe we can take the other common diseases of aging along with it, while we are at it.

Afterword

     The saddest, and sickest, part of this whole, pathetic dirge is that we had a correct outline of a coherent cancer metabolism theory; and a few central pathway assault systems, over thirty years ago. These are just being ‘rediscovered' today.  Only the future will tell us how much unnecessary time and life have been lost.Let us just hope that we will never suffer from the likes of such a ‘theory-bigotry' ever again.

 

Copyright: January 23, 2011 by

 

Gregory S. Bambeck Ph.D.                     

E mail: gregorybambeck at yahoo dot com

Michael Wolfson J.D., M.B.A.

E mail: mwolfson at stanfordalumni dot com 

      

About the Author

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