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Abstract  Conceptual models of epithelial carcinogenesis typically depict a sequence of heritable changes that give rise to a population of cells possessing the hallmarks of invasive cancer. We propose the evolutionary dynamics that give rise to the phenotypic properties of malignant cells must be understood within the context of specific selection forces generated by the microenvironment. This can be accomplished by using an “inverse problem” approach in which we use observed typical phenotypic traits of primary and metastatic cancers to infer the evolutionary dynamics. This has led to the hypothesis that heritable changes in genes controlling cellular proliferation, apoptosis, and senescence, while necessary, are not usually sufficient to produce an invasive cancer. In addition to these evolutionary steps, we propose that the common observation of aerobic glycolysis in human cancers indicates, via the inverse problem analysis, that adaptation to hypoxia and acidosis must be a major component of the carcinogenic sequence. The details of the hypothesis are based on recognition that premalignant populations evolve within ducts and remain separated from their blood supply by a basement membrane. As tumor cells proliferate into the lumen, diffusion-reaction kinetics enforced by this separation result in hypoxia and acidosis in regions of the tumor the most distant from the basement membrane. This produces new evolutionary selection forces that promote constitutive upregulation of glycolysis and resistance to acid-induced toxicity. We hypothesize that these phenotypic adaptations are critical late steps in carcinogenesis conferring proliferative advantages even in normoxic conditions by allowing the population to produce an acidic environment (through aerobic glycolysis) which is toxic to other local cell populations and promotes extracellular matrix degradation, increasing invasiveness. [ABSTRACT FROM AUTHOR]

Abstract  Investigating the causes of increased aerobic glycolysis in tumors (Warburg Effect) has gone in and out of fashion many times since it was first described almost a century ago. The field is currently in ascendance due to two factors. Over a million FDG-PET studies have unequivocally identified increased glucose uptake as a hallmark of metastatic cancer in humans. These observations, combined with new molecular insights with HIF-1α and c-myc, have rekindled an interest in this important phenotype. A preponderance of work has been focused on the molecular mechanisms underlying this effect, with the expectation that a mechanistic understanding may lead to novel therapeutic approaches. There is also an implicit assumption that a mechanistic understanding, although fundamentally reductionist, will nonetheless lead to a more profound teleological understanding of the need for altered metabolism in invasive cancers. In this communication, we describe an alternative approach that begins with teleology; i.e. adaptive landscapes and selection pressures that promote emergence of aerobic glycolysis during the somatic evolution of invasive cancer. Mathematical models and empirical observations are used to define the adaptive advantage of aerobic glycolysis that would explain its remarkable prevalence in human cancers. These studies have led to the hypothesis that increased consumption of glucose in metastatic lesions is not used for substantial energy production via Embden-Meyerhoff glycolysis, but rather for production of acid, which gives the cancer cells a competitive advantage for invasion. Alternative hypotheses, wherein the glucose is used for generation of reducing equivalents (NADPH) or anabolic precursors (ribose) are also discussed. [ABSTRACT FROM AUTHOR]