Mainstream Science's Dogma Reversal: Aerobic Glycolysis or Metabolic Alterations are finally seen as Compulsory for Cancer Cell Initiation or Maintenance. and Michael Wolfson J. Subsequent to a 1/2 of a century, mainstream large science has completely reversed its dogma on how it is compulsory that cancer cells partition their nutrient resources, in a critical way, between fabric for cell growth and life production. A thirty years ago modified version regarding the originally rejected Warburg theory, now has powerful help 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 methodology of cancer during this whole time span.
Only the future shall tell how many person suffering, should have been prevented, if just honest inquiry and scrutiny had also been allowed to flower, instead regarding the exclusionary and prejudicial pursuit of personal influence over pet investigative paradigms. Many precious time, knowledge and person 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 manage processes shall benefit us all, not only within the medicinal region of cancer, but in therapeutic arenas of some other primary diseases of aging, as well. A brief human, scientific, data and fact the past is contained, herein.
In a watershed reversal of an entrenched fifty 4 year old dogma, Science magazine published a Special Section issue on 12 or 03 or 10 devoted to metabolic energetics; and more so to diseases of aging, for example heart disease, diabetes II and especially, cancer. Most important, from a historical and this document's standpoint, is the story on p. 1340 by Levine and Puzio-Kuter, which concludes that key elements regarding the Warburg aerobic glycolysis hypothesis are critical to and compulsory for the initiation and maintenance regarding 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' should 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 should have been thought about heretical, and so taboo as to be refused publication in any primary scientific journal or to have received any studies funding by any respectable granting agency. This sorry story goes return to mid twentieth century. Consequently science itself should 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 display me', replicate to prove', and peer review crosscheck and verification safeguards of scientific inquiry should be swept distant within the emotional heat regarding the moment.
As such, was the fury and wholesale rejection surrounding the towering influence regarding 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 lone laboratories or in narrow parts of specialization, where it should be definitely shown that science moves forward more so in fits and starts, lurches and bounds and many times in haphazard random walks. Scientific disagreements usually take location without many beyond a little political ripples, as friendly or otherwise combatants ruffle each other's feathers on a one to one, or mini team basis. In short, things not ever 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 1/2 of a century, the subject of aerobic glycolysis was verboten; sealed with skull and crossbones. In 1956, Warburg's 3 valid hypotheses went below similar drain used to flush below his third imperfect hypothesis. More significantly, even the learn of general intermediary metabolism, itself, has moved into similar backwaters for the final 30 years. How and howcome 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 regarding the past and or or release credit where credit is due? What are the medicinal implications of our newly located logical reversal? Where do we leave from here?.
Answers to little of these questions, in component or more fully, are available within the Science story referenced within the 2nd sentence of this paper. We highly recommend that the reader look into this article, due to the fact that it ever so quietly represents probably the biggest biomedical upheaval, reversal and revolution in higher than a 1/2 century. This is no mini potatoes. We are seeing at a genuine historical paradigm shift of momentous dimensions, the historical importance, of which, aerobic glycolysis naysayers should wish to remain hidden within the attic, like a senile grandparent, due to the fact that the unquiet' story version is basically just too embarrassing. We have knowledge of this is true, due to the fact that two of us was there; lived it.
We take little different tack than Science, when answering such questions and while remembering the fifty-four year aformentioned history. We are going to talk little science, but the real heavy stuff we shall leave to reader to retrieve in our short, but highly informative reference list. Regardless, it helps to hold a simple background in metabolics, nutrition and bioenergetics or biochemistry 101. For the fewer technically initiated, scan over the science stuff, paying deeper attention to person 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 method a cell created the vital life carrier molecule, ATP, that is compulsory to force most cellular functions. In a normal cell, glucose is the primary fuel burned to make ATP. This occurs in 3 stages. First stage, called glycolysis, burns without oxygen, produces 3 ATP and feeds its product, pyruvate, into the 2nd stage, called the Kreb's-OX or PHOS system, which burns with oxygen and produces 32 ATP.
The 2nd system also creates 3 ATP without oxygen. Thus, in total, 4 ATP 12% result from burning without oxygen substrate phosphorylation and 32 ATP 88% are created by burning to carbon dioxide, with oxygen oxidative phosphorylation-OX or PHOS. Glycolysis occurs within the cell cytoplasm, while Kreb's-OX or PHOS occurs within 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 life death due to lack of ATP, the cell elevates glucose importation and the rate of glycolysis increases dramatically many times exceeding 1000% to make up for the ATP life production shortfall. When oxygen grades rise, the normal cell system returns return to its efficient 12 or 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 two elevated glycolysis, 3 elevated lactate production and 4 mitochondrial oxygen consumption deficiency. 3 that became the fly within the ointment. Scientists successfully attacked his mitochondrial respiratory defect concept due to the fact that many cancer cell mitochondria had normal respiration. Warburg countered that little mitochondrial numbers, on a per cell basis, should yield the conclusions seen, as it is the cell, that 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 higher than just a little variations of cancer cell mitochondria have normal respiratory chains and that a mini many cancers even display 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 prior to the days regarding the chemiosmotic hypothesis of Mitchell, and the concept of respiration being uncoupled from ATP was unknown and not readily measurable with the cutting edge designs regarding the times, so his knowledge error should be overlooked, but his assumption cannot, due to the fact that it was no more proven than its antithesis.
Even though Weinhouse was very wrong, he won the day. In fact, he won the next 4 decades, and even in 1999, metabolism was still not thought about in Hanahan and Weinberg's highly touted six hallmarks of cancer', even though by this time, convincing data to contrary had been available for higher 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 repeatedly to any degree of former glory. Moving his target from oxygen to 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 studies paradigm focus of cancer causation, while aerobic glycolysis was perceived like a mere effect of these greater' factors. By the time the 1980's rolled around, genomics, followed by massive DNA sequencing and mining within the 1990's, completely dominated the cancer studies agenda, to spot that their was no one left who should even do not forget thinking of cancer in metabolic terms. Below, we tell a brief story about someone who did ponder about it, and deeply.
Intermediate History: A Lone Case Study. About 20 years subsequent to the 1956 Warburg debacle, a young and very politically nave 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 within the early 1960's that allowed us to measure the actual many ATP produced per oxygen consumed in isolated mitochondria, which should measure to what degree ATP production was definitely linked coupled to oxygen consumption. In general, and without getting into details, mitochondria make 3 ATP per oxygen consumed when 100% coupled.
Anything fewer is thought about uncoupled,' and is expressed like a ratio of full coupling in terms regarding the ADP or O ratio; i. an ADP or O of 3 tells us that mitochondria are 67% coupled, or 33% uncoupled, as one may prefer it. Thus, uncoupled mitochondria are measurably ATP production deficient. Since our grad student only had a lone 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, many times employed by pure theoreticians.
What he did locate was that per cancer cell mitochondrial ATP production, was severely diminished in all cancer categories in which there were mitochondrial population, respiration and or or ADP or O data. He concluded that virtually all cancer cells may have decreased than normal Kreb's-OX or PHOS produced ATP like a result of two decreased than normal numbers of mitochondria per cell, 3 deficient respiration per mitochondria, 4 decreased Kreb's cycle or NADH production, 5 lowered coupling to OX or PHOS or six a combination of any 3 or more regarding the above. Whether the per cell mitochondrial ATP production shortfall was due to an intrinsic internal central system defect s within the actual mitochondrion itself or whether it was due to some external regulatory manage element s defect s did not matter, as long as the net output ATP deficiency was similar end result. By whatever means, should be present and on a per cell basis was the central mantra of his dissertation: Mitochondrial Alterations in a Lymphoblastic Lymphoma Transplanted into DBA or 1J Mice. He also showed how this compulsory aerobic glycolytic change should switch the whole regarding the panoply of intermediary metabolism into state of relentless cell growth, like a cause of cancer, and not an effect.
As we shall see, thirty years later, we finally have knowledge of all of these propositions to be true. This kid was not only nave he was a glutton for punishment. Between other things, he was an intermediary metabolism junkie. He memorized every chemical structure and reaction regarding the thousand plus biochemical components regarding the intermediary metabolic system and stared for endless hours, for over 3 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 clean to him that mitochondrial Kreb's-OX or PHOS ATP production deficiency, within the presence of glycolytic enhancement and pyruvate diversion to lactate, should shift the whole schematic toward anabolism in exactly the method compulsory to enforce irreversible cell growth, and to satisfy ATP requirements. Like a for instance, within the presence of dramatically enhanced glucose importation, elevated glycolytic fetal enzymes, pyruvate diversion and Kreb's-OX or PHOS deficiency, a many things must, and do, happen. Glucose becomes partitioned between glycolysis and the pentose phosphate shunt PPP, an anabolic drive system, which should 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 sends 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, not ever burn up all the ATP life in their formation, but conserve little of it as high life intermediates. This shall also be true of NADPH, which defuses highly mutagenic reactive oxygen species ROS from processes like uncoupled OX or PHOS. Our grad student also envisioned Kreb's-OX or PHOS ATP production inefficient mitochondria as participating within 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 give a balanced nitrogen substrate combine 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 like a glycolytic substrate phosphorylation and ATP generation synergizer or partial glycolytic alternative in cancers that were not rampantly glycolytic. He saw it as included within the nitrogen balance amino acid system. Yes, it shall also be 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.
Consequently there was virtually no studies on the topic at that time, our grad student was heartened to retrieve 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 should 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 4 hours, with 5TG and radiation while normal cells lived, and were definitely radiation protected! This shows the potential of a direct aerobic glycolytic pathway attack synergy with conventional therapy. Imagine how distant we should have sprint with a concept' ball like this by now, if we had only taken advantage regarding the 32 years ago head start, instead of possessing to rediscover' other glycolytic blocking agents in just the final little years.
With his unassailable' armaments in hand, our intrepid graduate student went to cell biology and physiology meetings for multiple years, only being allowed lowly poster sessions due to the fact that their were no symposia on the subject and no podium presentation space available for such topics. One should ponder that such a global hypothesis, with ancient debate resolving data and such stupendous differential cancer cell death rates, at least, should inspire debate. Between the young scientists, there was no debate due to the fact that they had no plan what the H he was talking about, most of them, not ever even possessing heard regarding the Warburg effect. Between the old guard, there was no debate due to the fact that 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 ever trust that crap anymore. kind of response, was more like a religious rejoinder than a scientific argument. His vague hopes of publication, at fewest 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. Possessing been un? duly castigated by the reigning Olympic gods of science, he assumed the appropriate insignificant insect' posture and opted to publish his dissertation below the aformentioned more humble title, as opposed to more strident version appearing subsequent to the colon within the title of this present article. Oh! Incidentally, his lymphoblastic lymphoma mitochondria were completely uncoupled, in direct opposition to full coupling of all normal tissues tested.
So, here we sit, thirty many too many years later, rediscovering' a brand new discovery! killing cancer through receiving advantage of its tasty 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 due to the fact that the field is now so unbelievably fallow. So, what has grow to of our insignificant insect'? He remains as unknown this day as he was thirty years ago, in spite regarding the fact that his postulates outlined a simple and direct, but adequately detailed description regarding the central metabolic and energetic framework sans glutamine, partial oops! that we now have knowledge of to be true. However, he finally has a sense of belated relief, now that a critical region of cancer studies is receiving its due scrutiny.
Scrutiny was no higher than what he was asking for, in 1980, within 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 regarding the ball of life science, while protein function, now called proteomics, became a wallflower. That is, by no means, an evil thing except for the proteomics part.
A new and bountiful harvest of knowledge, unlike anything ever seen within the life sciences, was being born. The DNA light of new understanding was burning so brightly as to blind, shock and awe'. Consequently hidden within the data storm, eventual salvation for aerobic glycolysis was grinding slowly, but relentlessly, through the return door. However, this should still take time. For the next 3 decades regarding the 80's and 90's, cancer cell metabolism investigation, now reduced to a sub-handmaiden to genomics, and already reeling from its first 3 decades of insult, was now in line for 20 more years regarding the same.
Even as late as 1999, Hanahan and Weinberg did not even mention metabolism in their well-known six hallmarks of cancer, those being: two growth signal self activation, 3 growth suppressor inhibition, 4 programmed cell suicide evasion anti-apoptosis, 5 immortalization, six sustained vascularization angiogenesis and seven metastatic tissue invasion. These shall have sounded done at the time, but it had been an extended cold winter for cancer metabolism, and things were about to change. Subsequent to the person genome project finished at the turn regarding the century, the scientific community woke up to an obvious next question. We have over 22,000 genes here, coding for proteins, the functions regarding the majority of which, we are clueless. What do the proteins that all these genes code for, definitely do? Subsequent to the turn regarding the millennium, this question should lead us back, full circle, to an actual serious and sober rethink of a modified Warburg hypothesis.
As unsympathetic as it shall sound, it helps that the old college knee jerk anti-Warburgians are now mostly gone, and aren't around to manipulate, bulldog' and sprint roughshod over contrary thought. In addition, a dearth of metabotypic data has permitted an special crop of open-minded scientists to arrive with unencumbered metabolic preconceptions onto a new playing field. What an special playing field it is! There now exists a profusion of data around cancer cell intermediary metabolic regulatory manage processes that should have had any graduate student from thirty years ago brimming in anticipation of understanding their significance. Little of this meaning is just coming into the light, like a new marriage between then and now, reminding us regarding the phrase; Something old, something new, something borrowed, something blue. Present History: The New Millennium.
During the final decade, since the turn regarding the millennium, the golden age of biology went from a promise to a reality. Not only has there been a zillion fold increase within the velocity of molecular, genomic and proteomic data collection, but there has also been a similar concomitant decrease within the cost per data spot collected. For example, within the final ten years, DNA sequencing has decreased its time or cost ratio from six years and $3 billion per genome to 3days and $10,000 per genome. 6% improvement in time and a 99. 996% reduction in cost that yields a 99.
9999%+ overall improvement in efficiency. This returns with a promise of a 100 times more efficiency increase over the next couple of years. Similarly, computational speed, memory and topic critical software have kept abreast with the barrage of genoproteomic and metabogenoproteomic information, and most noticeably, on a gene conservation evolutionary scale. Within the case in point, that being, our cancer metabolism discussion, a many deeper understanding regarding the huge and growing array of metabolic manage elements has led us to a more mechanistic understanding that a modified Warburg hypothesis is correct, and shall give us with, paradoxically, a smaller, but more powerful suite of differential cancer cell killing strategies and molecules. There shall also be evidence from now and thirty years ago, as the reader shall recall 5TG that these central pathway target molecules should synergize with decreased dose forms of existing chemotherapies that should confer fewer and milder side affects, and that they should dovetail with simple dietary and life-style changes.
In this brief review, we should be providing a kind of Cliff Notes' rendition regarding the regulatory manage metabotype system, as we now understand it, due to the fact that its interaction set is huge. Otherwise, this story should grow to a more burdensome tome than it already is. Instead, we shall later give about a handful of Wow! Gee-Whiz! BIG SCIENCE review articles, such that you not ever need to wade through very many regarding the professional muck' to obtain to real juice. Besides, their bibliographies give all the muck' that you should ever need. However, we trust that it is very pretty muck, so, have at it.
Shortly subsequent to the year 2000, the nutrient and life sensing regulatory metabolism manage papers began to grow, and then expand profoundly around 2005. Almost immediately thereafter, some regarding the regulatory pathways came into focus, and soon, the dam burst large open. By the latter component regarding 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 an special position of aerobic glycolysis creation, manage and dynamics.
This is a higher position of manipulation regarding similar 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, that shall also be true. The new notion is; that if we should identify the specifics regarding the system more rationally, and with a more diversified weapon set, we should do some serious damage to this sickness 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 conclusions tell us that there is very many of work yet to do, but with a plan. The good news is that we finally have knowledge of where we are going. If there was ever a time for the pharmaceutical businesses to stand tall, this is that time. If there was ever a time to throw a buck at cancer research, this is that time.
Creating use of cancer's own growth system against itself should be preferable to 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 story also registers a vote for the importance regarding the preservation regarding 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 located in a broad section of tumors. Purportedly, most 3BP and DCA kill cancers that cannot up regulate mitochondrial OX or 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 or PHOS for quiescent survival. Consequently most are preferable to full blown disease, cancer kill is preferable to growth stoppage, due to the fact that it eradicates the tumor, while growth arrest is more akin to resetting the clock on a time bomb, as an already mutated system basically awaits not many distant mutation, which shall or shall not happen. But, hey folks! At this point, we shall take any port in a storm. DCA is yielding conclusions in a broad array of pet cancers, and clinical trials are underway in person brain glioblastomas.
Preliminary conclusions are not brief of thrilling. We already discussed 5TG, as something old. Other aerobic glycolysis and mitochondrial blockers are within the works, as something new. In addition to core, or central metabolic pathways of aerobic glycolysis, an interwoven and layered set of regulatory pathways manage the central pathways. Genetic errors within the regulatory pathways can force the central pathways to obtain stuck' within the cancer metabotype.
Blockers, rectifiers and mutations in these pathways institute similar or similar effects as seen by blockers, rectifiers and mutations within the central pathways. For example, when driven by mutated nutrient sensing growth signals or repressed by activated mutant life sensing growth suppressor signals, aerobic glycolysis is instituted, and multiple benign tumors result, in pet models. Eventually, these new highly ROS enhanced, and therefore, mutagenic tumors, leave metastatic. Throwing a monkey wrench into this aerobic glycolysis activated system can kill the cancer, but spares normal cells, due to the fact that they can be adaptable. If there is anything approaching a metabolic first manage element within the nutrient fuel and life sensing metabolic regulatory system, it is target of rapamycin TOR.
An actvated TOR switches the system toward nutrient importation, OX or PHOS inefficient anabolism and cell growth, while an inhibited TOR switches the system toward internal metabolite recycling, OX or PHOS efficient catabolism and cell quiescence. Like a spider within the center of a web, with all legs tuned to a host of quivering silk strands, TOR performs a balancing act between the components of a huge array of lone inputs from an integrated cross-talking' set of metabolic status sensors. Then, it activates and represses, in turn, gene activators and repressors of multiple 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 multiple principle variations of homeostatic drive states for example cell growth and division, quiescence, response to starvation, ROS load and cell component stress damage. The elucidation regarding the regulatory TOR affected and effected processes are what finally cemented the modified Warburg concepts into stone.
Briefly, the cell growth factor nutrient sensing IGF or P13K or AkT or TOR pathway upregulates HIF to stimulate anaerobic glycolysis and PGC-1alpha to institute mitochondrial neogenesis, which creates new, but OX or 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 or 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 3 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 have knowledge of that 3 of Hanahan and Weinberg's six hallmarks of cancer shape a singular direct TOR processes link to aerobic glycolysis. The fact that the immortalizing ribonucleoprotein, telomerase, relocates from the mitochondria to nucleus below 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 below regulates the apoptotic cell suicide program, in addition to notion that growth rate progression and metastatic invasion typically correlate with a progressively more ruthless aerobic glycolysis drive state, as adjuncts to final 3 hallmarks, cannot be overlooked. In spite regarding the thousands of mutated oncophenotypes that plague our present cancer cell miasma, the modified Warburg effect remains the highest many central, consistent, and universal hallmark' of pre-cancerous hyperplasia, cancer cell initiation, cancer cell maintenance and cancer cell progression that we have knowledge of of.
Maybe, we need fewer hallmarks and fewer assumption. Now, Weinhouse and Weinberg are most wrong. The Wein' methodology followers should, by now, be retreating from their dogma. Even with a virtual absence of knowledge regarding the external regulatory interactions between Kreb's-OX or PHOS and glycolysis, in 1980, the system, at that time, was conceivable from its central elements alone. This was likely for our grad student, due to the fact that 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 or PHOS inefficient neogenesis and Kreb's-OX or PHOS efficient regenesis is real illuminating, particularly in helping to understand more esoteric regulatory features than those provided within the 1980 hypothesis. For the people 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 like a Lone Controllable Molecular Pathway, by Bambeck and Wolfson, which should be look for engined on the internet. For the people who wish to plunge eyeball deep' into these systems, they can look up the following articles: Z. Feng, Cold Springs Harbor Lab Press, 2010 p. Sonenberg, Science, 327, 4 or six or 10 p.
, Science, 328, 5 or 16 or 10, p. Sheldon, Nutrition and Metabolism, 7,7, two or 27 or 10; and for multiple papers and articles, Science, Special Section, 4 or 12 or 10, p. Look for engine phrase sets like AMPK-TOR-cancer; mitochondrial regenesis or neogenesis; Bambeck-cancer and or or life extension; caloric restriction pathway; aerobic glycolysis-Warburg and other obvious look for engine words in this story shall get you to anywhere you need to go. The first reason that there is such a recent explosion of work on the nutrient sensing IGF or P13K or AkT or TORc1 or HIF and its converse life and stress sensing p53 or AMPK or TORc2 or ROS or FOXO or SESN loop pathways has to do with the fact that they cast such a broad net. First, they can be highly conserved within the evolutionary tree, from yeast to humans.
Second, they integrate throughout a large array of sickness versus health, conditions. The cancer metabotype is just the tip of this iceberg, albeit being one damn large tip; large enough for it to be a mega-topic all its own. The relative ease and simplicity of controlled manipulation regarding 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. Within cancer, these diseases or conditions are many times referred to as the diseases of aging,' and account for a whopping 85% of all death within the developing and developed world. Probably the highest many surprising discovery of all is that up regulation regarding the AMPK or TOR or SESN loop initiates genuine life extension beyond the normal maximum via caloric restriction CR.
Even more astounding is that CR mimetics for example metformin an AMPK activator and anti-diabetes II drug, rapamycin a TOR inhibitor and anti-tissue rejection factor and perhaps, high bioavailability' resveratrol an usual dietary supplement, AMPK activator and anti-oxidant, fight all of these primary diseases. They reduce diabetes severity via increased insulin sensitivity, inhibit cancer cell metabotype formation as previously described, promote mass 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 regarding the above things described. We talk in more detail related to the life extension pathway in our aforementioned publication. These diseases already strain our local budget to breaking point, and threaten to undermine and overwhelm our economy within the next decade or two. With our present economy spending almost a fifth of its GDP on medicine, we have not ever been in more need regarding the proverbial clean knight in shining armor.
Well folks, this just may be that clean knight, albeit a rather historically beaten, bruised, tarnished, but finally renewed and reinvigorated clean 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 return to similar to hellhole where it came from. Maybe we can take the other common diseases of aging along with it, while we are at it. The saddest, and sickest, component of this whole, pathetic dirge is that we had a correct outline of a coherent cancer metabolism theory; and a little central pathway assault systems, over thirty years ago. These are just being rediscovered' today.
Only the future shall tell us how many unnecessary time and life have been lost. Let us just hope that we shall not ever suffer from the likes of such a theory-bigotry' ever again. E mail: gregorybambeck at yahoo dot com. Email: mwolfson at stanfordalumni dot com.
