Infamilialadenomatouspolyposissyndrome,inheritanceofagermlinemutationintheAPC geneandsporadiclossofthesolenormalallelecausesthedevelopmentofhundredsofcolonicpolypsatayoungage.Inevitably,oneormoreofthesepolypsevolvesintoacoloniccancer.SomaticlossofbothallelesoftheAPC geneisseeninapproximately70%ofsporadiccoloncancers.
Even in the presence of ample oxygen, cancer cells demonstrate a distinctive form of cellular metabolism characterized by high levels of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway. This phenomenon, called the Warburg effect and also known as aerobic glycolysis, has been recognized for many years (indeed, Otto Warburg received the Nobel Prize in 1931 for its discovery). Clinically, the “glucose-hunger” of tumors is used to visualize tumors via positron emission tomography (PET) scanning, in which patients are injected with 18F-fluorodeoxyglucose, a glucose derivative that is preferentially taken up into tumor cells (as well as normal, actively dividing tissues such as the bone marrow). Most tumors are PET-positive, and rapidly growing ones are markedly so.
Warburg’s discovery was largely neglected for many years, but over the past decade, metabolism has become one of the most active areas of cancer research. Metabolic pathways (like signaling pathways) in normal and cancer cells are still being elucidated, and the details are complex, but at the heart of the Warburg effect lies a simple question: why is it advantageous for a cancer cell to rely on seemingly inefficient glycolysis (which generates two molecules of ATP per molecule of glucose) instead of oxidative phosphorylation (which generates up to 36 molecules of ATP per molecule of glucose)? While pondering this question, it is important to recognize that rapidly proliferating normal cells, such as in embryonic tissues and lymphocytes during immune responses, also rely on aerobic fermentation. Thus, “Warburg metabolism” is not cancer specific, but instead is a general property of growing cells that becomes “fixed” in cancer cells.
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The answer to this riddle is simple: Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not. The reason growing cells rely on aerobic glycolysis becomes readily apparent when one considers that a growing cell has a strict biosynthetic requirement; it must duplicate all of its cellular components—DNA, RNA, proteins, lipid, and organelles—before it can divide and produce two daughter cells. While oxidative phosphorylation yields abundant ATP, it fails to produce any carbon moieties that can be used to build the cellular components needed for growth (proteins, lipids, and nucleic acids). Even cells that are not actively growing must shunt some metabolic intermediates away from oxidative phosphorylation in order to synthesize macromolecules that are needed for cellular maintenance.