A group of leading oncologists and researchers in the field of Basic and Clinical Oncology ", has decided to send DSALUD Discovery through an" open letter "to Dr. Mariano Barbacid, director of the National Cancer Research Centre (CNIO) - in asking him to respond publicly to a number of issues of vital importance in the context of current cancer research and say whether you agree that it is time to become a global restructuring of this disease, especially as far as coping strategy, referred to as the failure of current medical treatment in most malignant tumors. The signatories are members of the International Society for Proton Dynamics of Cancer (ISPDC)-International Society for the Dynamics of Protons in the Treatment of Cancer (www.ispdc.net) - and among them are the president and vice president of the organization.
OPEN LETTER TO DR. Mariano Barbacid
of oncologists and researchers
Salvador Harguindey, Stephan J. Reshkin, Miriam L. Wahl and Stefano Fais
On 24 October The two English TV gave a long interview with Dr. Mariano Barbacid, director of the National Cancer Research Centre (CNIO) - in which he offered a vision of orthodox cancer still shared by many researchers and oncologists in Spain and abroad. In the interview Barbacid-doctor in Chemistry, said that in fact "cancer" is a word that encompasses a generic "more than 200 different diseases," suggesting that this is why many more will be needed to discover new drugs because each one of these diseases should be treated differently and individually.
Well, the signatories of this letter, oncologists and researchers, we understand that this statement corresponds to an outdated view of cancer that is directly contrary to modern oncology paradigm emerged in a few years ago. The new perspective, by contrast, plays and has been shown that all "types" of cancer and leukemia are more common features than differences. A worldview is able to see "what's in the special"-something that since Claude Bernard has been the main mission of medical science in order to incorporate the most advanced and all the facts and figures scattered within the new paradigm. This new worldview was already considered in 2000 by Douglas Hanahan and Robert A. Weinberg in his well known review The Hallmarks of Cancer published in Cell, vol. 100, 57-70, 2000. Text that literally stated as follows: "This disease will continue the case in the same way the next quarter century and in the same line that has been in the recent past by adding more layers of difficulty to a scientific literature that has reached limits of complexity almost impossible to measure. But we anticipate something different: these people, the problem of cancer research, practice a kind of science quite different from what we experienced in the past 25 years. And I'm sure that change will be apparent at the technical level but, ultimately, fundamental changes are conceptual in nature (emphasis ours). We anticipate that cancer research evolve into a science where logic prevails and the complexities of the disease, described in the laboratory and the clinic, will be understandable in terms of a few underlying principles, some of which are currently close to being decoded. In our review, we discuss a set of them, especially the rules that explain the transformation of normal and malignant human cells. Our suggestion is that research in recent decades has revealed that a small number of cellular and biochemical-molecular-acquired skills that share most, if not all human cancers. Our faith in this simplification stems directly from the teachings of cell biology that says that virtually all animal cells have a similar molecular machinery that regulates their proliferation, differentiation, and death. " Knowing
which we can ask both Dr. Barbacid and those who still share with him the same reductionist and divisive worldview cancer what you really know most researchers now on the intimate and essential nature of neoplastic diseases to support the cancer are "200 different diseases." Is the golden rule of medicine that just getting to the root, to the notion underlying health problem You can access a rational understanding and correct interpretation of a pathology, a step essential for both preventing and aspire to properly treat once it has arisen. Without knowing the cause or root causes (etiology), the intermediary mechanisms (pathogenesis) and the very essence of a disease (nature) can not even think about overcoming it. And this is so especially in this case because, as I said the father of the biochemistry of cancer, Otto Warburg, "we can only heal what we can understand first."
is therefore of interest that Dr. Barbacid justify publicly their opinion answering, commenting or contradicting the following questions:
1) In what basis to assert that the word cancer refers to 200 different diseases when all cancer cells have the same morphological and pathological features framed within the terms "dysplasia." All the cancer cells of any origin-location and have the same features of cellular atypia are: a) loss of nucleus / cytoplasm, b) loss of polarity, c) increasing the number of mitoses, typical or not; d) nuclear pleomorphism and hyperchromatic. In general can mimic the tissue of origin except in the most undifferentiated.
2) How is justified, then, that all cancer cells of any tumor type and genetic background have the same biochemical characteristics and energy, as the exaggerated consumption of glucose ("first law of Biochemistry of Cancer" from the time of Warburg), and why are all sugar consumed in the presence of oxygen, although some more than others, depending on its degree of this malignancy? Clearly
interpreted from a genetic point of view leads to cancer represent it as an overwhelming and daunting variety of illnesses requiring a vast range of therapeutic strategies and a countless number of designated substances to treat each and every one of malignant tumors. But when this is analyzed phenotypically it is found that all cancers share a variety of distinctive features at different levels and biochemical, molecular, physiological and metabolic energy-independent of tissue origin and their different genetic backgrounds (Harguindey et al., BBA ROC, 2005, Cardone et al., Nature Revs. Cancer, 2005). And that means, or at least suggests, the existence of a common mechanism underlying transformation and tumor progression. Therefore, a proper antineoplastic therapy can not ignore. Hence, scientists of the stature of Professor Jacques Pouysségur claim that there is enough evidence to consider the specific abnormal metabolism of all the cancer cells of any strain and origin-as the "Achilles heel" of cancer, which gives us the opportunity to manipulate and use those differences to make a profit treatment selectively (Kroemer G. & J. Pouysségur, Cancer Cell, 2008).
3) Why all the cancerous cells and tissues beyond their genetic type and we insist, have the same homeostatic disruption of energy metabolism that is completely different from all normal tissues? That is, an aberrant regulation of the dynamics of hydrogen ion leads to a reversal of the pH gradient in all cancerous tissues and cells (ΔpHi to ΔpHe) which is even opposed to the extracellular pH gradients / intracellular normal cells and tissues. A reversal pathological absolutely specific for malignancy, and that, therefore, does not happen in any other known situation, which is considered one of the distinguishing characteristics that define the molecular mechanisms of tumor energy, even being seen by many as the master of them all, and is also beyond any type of tumor pathology or genetic origin.
In summary, the reversal of the dynamics of H + through the tumor cell membrane is shown as the differential molecular feature that separates definitely all cancerous cells and tissues of each and all normal. This is known as "the neoestrategia of cancerous tissues and cells," goes far beyond a simple change of pH. However, from the point of view of cellular energy is the most brutal possible disruption of the microenvironment and the nature and behavior of cells that can be imagined, determining the natural history of the tumor and being in the world of biology, equivalent in its determinism, physical impact and epigenetic consequences to an extraordinarily deterministic and unstoppable chain reaction.
4) It is often said that "widespread in the field of oncology is impossible and yet it is clear that now is possible: just go to the root and trunk of the disease instead of beating around the bush . How do you explain the fact that all the cancer cells of any origin, share many other events and differential selective cancer properties that also separates them clearly and without exception all normal cells)? At least seven the behavioral alterations in cell physiology that dictate the determinism of all growth tumor. Namely:
1) Self-sufficiency in growth signals.
2) insensitivity to growth inhibitory signals or anti-growth signals.
3) evasion of cell death program (apoptosis).
4) unlimited replicative potential.
5) sustained angiogenesis.
6) the ability of invasion and metastasis.
7) A potentially eternal nature.
Each of these changes, also the new skills acquired during tumor development, represents the successful breaking of a defense mechanism deeply rooted in the cells and tissues of the body, assuming an apparent failure of nature. Hanahan and Weinberg postulate that these capabilities are shared by most, probably all, of human malignant tumors. And every cell type, either malignant solid tumors or leukemia, is governed and directed by the compendium of skills and solid preset rules.
5) Why do all the cancer cells from any source and origin, share the following specific metabolic principles are also targeted to pre-tumor progression? Namely:
1. Intracellular alkalosis.
2. Extracellular acidosis.
3. Reversal of the dynamics of proton intra / extracellular gradient of protons or ic / ec
4. Silent gene expression (eg transcriptase versa).
5. Increased glycolytic metabolism.
6. Aerobic glycolysis.
7. Cannibalism.
8. Overexpression of proton transporters and ion exchangers.
9. Increased release of exosomes.
6) How does it fit the official worldview shattered the current uniform and comprehensive interpretation of malignancies has been published in prestigious international journals Nature, Cancer, Cancer Research, FASEB, BBA ROC, Nature Revs and others, which houses a unique perspective on major areas of cancer research, from basic to the clinics, including including the pathogenesis, metabolism the cancer cell resistance to multiple anticancer drugs (MDR) tumor neovascularization, the metastatic process, the selective apoptosis and antiapoptosis, cancer chemotherapy, and even the phenomenon of spontaneous regression of cancer?
7) Do not agree with Dr. Barbacid the prestigious journal Nature agreed to publish in 2009 the famous article by Robert A. Gatenby, also a member of the ISPDC-in which he acknowledged that "the war against cancer has been lost? Because this assumption is based on the recognition that the worldview held by those who believe that there are 200 different diseases behind the word cancer is no longer tenable. The conceptual paradigm and approach taken to date is dead. It was necessary to reconsider everything you think you know about this disease from the roots before they have managed to integrate its many faces and branches within the tree of knowledge of a higher unity, the "emerging paradigm."
8) Can not or do not want-to-understand yet that has reached the time for cancer research professionals around the world become aware of this reality and to be familiar with the keys as soon as the major energy systems and specific abnormal functioning of all cells and malignant tumors? Such as the aforementioned "reversal of the proton gradient, energy phenomenon also known as" proton gradient reversal cancer? A process that is governed by a series of proton pumps and transporters expressed and hyperactive super-sites in the cell membrane as the primary tumor and specific energy characteristic of cancer. Those who for many years understand these facts recognize what it all really means that a focus on target to inhibit the very abnormal dynamics of these processes in concert and specifically listed as a selective approach to cancer treatment in general . Line is research already has thousands of recognized publications in this field and is opening new and different paths to a more effective therapeutic and less toxic, possibly, all neoplastic diseases, or at least all solid tumors.
Perhaps the time has come, or is closer-that basic and clinical oncologists to get to wake up and decided to propose alternatives and at the same time, to muster the necessary inspiration, generosity and courage to stop living enslaved and captivated by the Big Brother of Oncology that constitute major multinational pharmaceutical companies, entities of questionable ethics to which only care about their economic interests and whose dynamics and motivations, which often lead to pseudo-try by all means to market ever more toxic medications, less effective and more expensive (V. Huber et al. J. Transl. Med 8 :57-61, 2010). While dedicated to fund clinical trials that border on the most irrational and absurd, such as promoting the use of agents to inhibit tumor neovascularization, a correct approach for prevention or in very early stages of the disease, but virtually never in patients preterminal when tumor neovascularization and the metastatic process and have been concluded in its role annihilating.
9) Returning to the scientific basis of the new holistic view also seems inexplicable to us today that most professional oncology research and practice are not yet familiar with four basic realities as indisputable as:
A) That the transformation of normal cells and tissues, irrespective of their origin or body-cancerous settlement occurs when the inside is alkalinized by the most varied methods.
B) The super-expression and hyperactivity of transporters and pumps in the cell membrane play a key asset in both the source and root cause as in tumor development subsequent local invasion from the activity and metastatic progression of all malignant tumors. Not only that, but that these same biochemical abnormalities play a very dynamic and inhibit negative host defense mechanisms (angiogenesis, spontaneous regression, MDR, etc.) Reversing the normal gradient of protons and thus induce an alteration - until now irreversible-thermodynamics of cell. In fact, tumor interstitial acidification induced in all malignant tumors, which due to the release of excessive protons of all malignant cells is of fundamental importance in the establishment, activity and progression metastatic process itself.
C) The concerted and progressive inhibition of these transporters of protons is a relatively new, unique and very promising in the search for selective anti-cancer treatments that are useful in preventing, delaying or even completely offset all the neoplastic process and strategy intrinsic to their different levels, from the etiology to treatment.
D) The joint use, progressive and concerted cellular transport inhibitors / extracellular protons or PTI (the "proton transport inhibitors) is another largely unexplored area (e) and largely ignored by the official oncology, both as single treatment or in combination with other forms of chemotherapy, being now in clinical stage also very promising and that seems essential in the treatment-whether primary, co-adjuvant or adjuvant-of various solid tumors in humans. In the same vein, prominent researchers in this field have recently advanced the concept of leading publications such therapeutic approach "will lead to a collapse and massive atrophy of solid tumors (J. Pouysségur, Nature, 2007). The currently available evidence indicates that this can take place beyond all differences and pathologic or etiopathogenic origin genetic of all malignancies.
In sum, the undersigned postulate a new paradigm integral, unitary and radical of neoplastic diseases by understanding that all malignant tumors are more factors in common than differences between them, as has been agreed at the recent First International Congress of Society for the Study of Proton Dynamics in Cancer held in early September in Rome (www.ispdc.com). This requires a shift, too radically, the current analytical-reductionist model disintegrated insists that the word cancer refers to more than 200 different diseases that must be treated with many drug combinations different even today that chemotherapeutic agents have proved more toxic than effective, except for germ cell tumors and some leukemias and lymphomas, tumors that make up a very small minority within the set of all malignancies. And that means that persist in the beaten path can only delve further into the mainstream therapeutic failure of current medical oncology at the same time prevent and stop any possible progress and real progress.
Signatories: Dr. Salvador Harguindey
Institute of Clinical Biology and Metabolism (IBCM), Vitoria.
Vice President of the International Society for the Dynamics of Protons in Cancer Treatment (ISPDC). Dr. Stephan J.
Reshkin Professor, Department of General and Environmental Physiology, University of Bari (Italy). Director of the Laboratory of Cancer Biology and metastasis
Dr. Miriam L. Wahl
Former Director of the Laboratory of Tumor pH Duke University (North Carolina, USA) and Associate Member of the Faculty of Medicine of the University of Baltimore (Baltimore, USA). Dr. Stefano Fais
President of the International Society for the Dynamics of Protons in the Treatment of Cancer (ISPDC). Director of the Antitumor Drug Section of the Department of Therapeutic Research and Evaluation of Medicine of the National Institute of Health in Rome (Italy).
