Robert A Gatenby

..382}. These predicted growth effects have a biological basis in the known presence of multiple alleles during cancer growth...

..Many fascinating challenges remain, including defining the intercellular information dynamics of multicellular organisms and the role of disordered information storage and flow in disease...

..Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer...

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..The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers...

..This model provides a theoretical framework in which the diverse cancer genotypes and phenotypes can be understood according to their roles as adaptive strategies to overcome specific microenvironmental growth constraints...

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..Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion...

..These previously unknown substrate dynamics in the later stages of carcinogenesis provide a mechanism for evolution of cellular properties typically found in invasive cancers including the angiogenic and glycolytic phenotypes...

..Furthermore, the models demonstrate that administration of cytotoxic therapies will, by reducing the tumor population density, create system dynamics more conducive to perturbations by biological modifiers...

..Rather, sporadic clinical cancers are emergent structures produced by multiple, fundamentally nondeterministic genetic pathways...

..The consequent unrestrained proliferation allows the glycolytic phenotype to emerge simultaneous with the transition from a premalignant lesion to an invasive cancer...

..0007). This is generally consistent with the predictions of the mathematical models. If confirmed, these results suggest novel and broadly applicable tumor therapies...

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..Specifically we propose that glycolysis is elevated because it produces acid, which provides an evolutionary advantage to cancer cells vis-à-vis normal parenchyma into which they invade...

..Glycolysis was affected by pharmacological regulation of c-Myc and HIF-1alpha. These findings suggest that c-Myc and/or HIF-1alpha activities are both involved in the regulation of glycolysis in breast cancers...

..Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease...

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..These results reinforce the hypothesis that acidosis promotes selection of stable, more invasive phenotypes, rather than inductive changes, which would be reversible...

..Living systems use information and energy to maintain stable entropy while far from thermodynamic equilibrium. The underlying first principles have not been established...

..Alternative hypotheses, wherein the glucose is used for generation of reducing equivalents (NADPH) or anabolic precursors (ribose) are also discussed...

..We propose this phenotype is critical for subsequent malignant growth of primary and metastatic cancers...

..A number of approaches have been proposed to solve this problem and, once it is solved, pH imaging methods will be applicable to human clinical pathologies...

..The simulations provide insight into the underlying cellular and microenvironmental dynamics that govern these empirical observations and suggest novel prevention strategies that may be tested experimentally...

..The abnormal microenvironment results in the selective survival and proliferation of malignant cells at the expense of contiguous normal cell populations...

..Finally, an application to cell growth during enforced distortion shows that a single hydrocarbon chain can be distorted into a membrane having equal order or complexity. Such membranes are prime constituents of living cells...

..These sources are conjectured to be cellular DNA and cellular transmembrane ion gradients...

..Examples are given of Hartree systems that obey the population dynamics of required predator-prey systems...

..We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer...

..Empirical evidence supporting this "acid-mediated tumour invasion" model is discussed...

..An acellular gap at the tumour host interface is also predicted and can be demonstrated in pathologic specimens. Novel treatment approaches based on this model are discussed...

..Analysis of the model allows us to assess novel therapies directed towards changing the level of acidity within the tumour...

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