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A Unitarian Biochemical and Bioenergetic
Theory of Adaptive Oncogenesis:
from hypoxia and energy starvation (aerobic and ambipolar)
to the roles of HIF-1, IGF-I, and Vitamins C and D

by Correa, Paulo N. & Correa, Alexandra N.
Aurora Biophysics Research Institute

J Biophys Hematol Oncol, Volume 1, Issue 5 (May 2010),  pp. 1-93

Article ID:   JBHO01-05-01

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The Journal of Biophysics, Hematology and Oncology is an open-review journal. If you wish to contribute a review of this article, please send your review to   editor.JBHO@aetherometry.com .


The present communication unites in a novel model of the etiology of cancer very diverse contributions to oncology made since discovery of the Warburg effect. The model proposes a unitarian understanding of acquired malignancy as a neo-lamarckian adaptive disorder whereby a cell escapes organism and tissue regulatory controls to adapt to a condition of energy starvation (embodied in a variety of oncogenic pressures that are hypoxic or hypoxia-like in their effects), by abandoning its normal aerobic metabolism and by altering its growth-factor responses to support hyperplastic and neoplastic proliferation, and block normal differentiation. The multifactorial role of oxygen in normal metabolism is underlined by the biological and biophysical effects of its chronic lack in the initiation and promotion of oncogenesis: via the hypoxia-inducible factors (and especially HIF-1), hypoxia activates glycolysis and shuts down oxidative phosphorylation; and it adversely affects not only the oxygen transport roles of hemoglobin and myoglobin, but also their thermal dissipation of absorbed radiant energy, an essential contribution to temperature regulation in homotherms. Nonhypoxic factors may have similar hypoxia-like effects. Lack of vitamin C and iron can block progression of the Krebs cycle, and shut down aerobic respiration. Copper, according to our model of the respiratory chain, may actually work in vivo as a respiratory poison. Altered growth factor regulation (e.g. decreased plasma concentrations of erythropoietin) or enzymic defects (e.g. lack of citrate synthase) may also induce hypoxia-like effects.

Moreover, according to the analysis we present here, poor oxygenation prevents absorption of the radiant energy needed to inject into the respiratory chain. We propose that absorption of solar- sourced radiant energy in the terrestrial environment - with an ambipolar energy spectrum of 28 to 79 keV - is a key modulating function of biological systems involved in the normal activities of hemoglobin, myoglobin, the cytochrome c oxidase complex, skin production of vitamin D3 and the differential radiant energy sensors of pinealocytes. It provides the energy thermally dissipated by hemoglobin and myoglobin, as well as the activation energy needed to initiate and terminate the respiratory chain, and thus the kinetic energy of the electrons and protons shuttled across mitochondrial membranes. Insufficient absorption of ambipolar energy is tied in to the causation of acquired cancer and, as suggested by the present etiological model, also connected to the deregulation of the Pasteur effect that permits manifestation of the Warburg effect. However, the latter is far from being a universal trait of cancer cells. Recent results by Jacques Sonveaux's group have shown that neoplastic phenotypes are distributed inside a tumor according to an oxygen gradient between lactic fermenters and lactic respirers, with their association being symbiotic. Our model suggests that this is best understood as functions of a unitarian auto-oncogenic vector of cumulative transformations for acquired cancers, and that this vector repeatedly invokes a recursive cell-regulatory circuit, the IGF (insulin-like growth factor) axis, in its effort to de-stabilize the autonomic control of the cell cycle.

At initiation of cancer, aerobic respiration is shut down substantially or entirely, and glycolysis is activated along with lactate dehydrogenase A (LDHA)-driven fermentation, to sustain hyperplastic proliferation and block differentiation. These metabolic shunts are brought about by the HIF axis (in particular by HIF-1) and modulated by the IGF axis (in particular by IGF-I, its binding proteins and its receptor, IGF-IR). They likely involve specific hypersensitive growth factor responses modulated by the IGF axis, including IGF-I hypersensitivity itself as found in Polycythemia vera. Such responses involve both epigenetic and post-adaptive alterations. With progression of the auto-oncogenic vector from hyperplasia to neoplasia, something akin to a differentiation of malignantly transformed states takes place which appears to require, in either case, changes in the IGF axis that render its operation independent from physiological control by its ligands, in particular from control by IGF-I, so that the orthosympathetic signals of the IGF axis become permanently turned on and the cell now exerts an organism-independent control over its own cycling. At this juncture, the oncogenic vector undergoes a split. The Pasteur effect coupling glycolysis to aerobic metabolism is severed in both instances of "neoplastic differentiation", but while the more aggressive neoplastic cells to which the Warburg effect applies rely solely on further acceleration of lactate production, other neoplastic cells adapt to the acidification of tumors - and blood - by turning on LDHB to employ the lactate as substrate, via conversion to pyruvate, for their mitochondrial Krebs cycle and respiratory chain. In solid tumors, the lactic respirers activate vascular endothelial growth factor production (controlled by the IGF axis) to stimulate tumor angiogenesis and thus acquire direct access to oxygen from the blood. Ultimately, the lactate fermenters become the highly-tumorigenic metastatic elements of terminal cancer.

We also suggest that serious clinical investigation with properly staged cancer patients should henceforth target the use of novel, or heretofore improperly-tested, non-cytotoxic treatments based on the presently proposed aetherometric model of auto-oncogenesis.