A return to cancer metabolism

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

“…However, to what extent these physiological roles are still assumed by astrocytes once they are transformed into astrocytomas has not been elucidated. Nevertheless, recent new evidence suggests that cancer cells, and to a lesser known extent astrocytomas too, exhibit metabolic adaptation and other phenotypic alterations that allow them to survive, proliferate, and invade into their surrounding space occupied by normal cells/tissues (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008). Metabolic adaptation and/or reprogramming in cancer cells in general and astrocytoma/glioblastoma in particular: As early as the 1920's, Otto Warburg and his associates were the first to note that cancer cells appear to depend on glycolysis for energy production and survival even though oxygen is not in short supply.…”

“…Warburg's extensive investigation into the metabolic characteristics of multiple types of cancer cells prompted him to hypothesize that cancer cells reply on glycolysis for energy supply because their mitochondrial oxidative metabolism is dysfunctional (Warburg, 1956). His hypothesis has been neglected for some 80 years until the recent resurgence of interests in "the role metabolic reprogramming in cancer progression" (Semenza, 2011). The recent "renaissance of the Warburg Hypothesis" (Warburg et al, 1927, Warburg, 1956) has stimulated a new era in elucidating the aggressive nature of many malignant tumors (including glioblastoma) and their purported dependence on glycolysis for energy and survival (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008).…”

“…His hypothesis has been neglected for some 80 years until the recent resurgence of interests in "the role metabolic reprogramming in cancer progression" (Semenza, 2011). The recent "renaissance of the Warburg Hypothesis" (Warburg et al, 1927, Warburg, 1956) has stimulated a new era in elucidating the aggressive nature of many malignant tumors (including glioblastoma) and their purported dependence on glycolysis for energy and survival (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008). While numerous studies have documented mutations in mitochondrial DNA (mtDNA) in a variety of cancers (Czarnecka & Bartnik, 2009) can thus tentatively provide a mechanistic connection to dysfunctional mitochondrial oxidative metabolism as predicted by the Warburg hypothesis, other recent evidence suggests this aspect of the Warburg hypothesis requires critical re-appraisal (Bayley & Devilee, 2010;Dang et al, 2011;Frezza et al, 2011;Ordys et al, 2010;Srivastava & Moraes, 2009).…”

“…Technological advances that can be exploited to treat glioblastoma: As already alluded to above, the recent "renaissance of the Warburg Hypothesis" has stimulated much research into cancer cell metabolism (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008). Indeed, the presumed dependence of cancer cells on glycolysis for cancer cell growth and proliferation has prompted much new investigation into exploring the glycolytic pathway as a new target for anti-cancer drug discovery (Bhardwaj et al, 2010;Chatterji et al, 2007;Chatterji et al, 2009;Lai et al, 2008;Lino & Merlo, 2009).…”

“…Magnetic resonance spectroscopy to elucidate metabolic adaptations/alterations in glioblastoma: High lactate accumulation, despite adequate oxygen availability, is a metabolic pattern commonly associated with malignant transformation of the uncontrolled dividing cell. This metabolic phenotype, termed aerobic glycolysis and historically known as the Warburg effect, is characterized by high glycolytic rates and reduced mitochondrial oxidation (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008), features that favor cell survival in the hypoxic microenvironments found in tumors. This phenotype also favors the routing of key metabolic intermediates away from oxidative metabolism and toward anabolic processes required by rapidly dividing cells (McFate et al, 2008).…”