Weareenteringintoaneraofre-awakeningoftheimportanceandinterestinthe role ofaltered intermediary metabolisminthedevelopmentandprogressionof malignancy. Therefore, thisbookMitochondriaandCanceristimelyandrelevant tocontemporaryandfutureresearch, training, andeducation. Thehallmarkstudies ofOttoWarburgetal. (1926)sparkedtheeraoftumorcellmetabolism. Fromthen untilaround1980, studiesofintermediarymetabolismofnormalandmalignant cellsweremajorareasofresearchandofgraduateandpostgraduatetrainingin biomedicalsciences. Thisperiodwasdominatedbymitochondrialstudiesandby thoseextraordinaryoutstandingscientistswhowereaffectionatelyreferredtoasthe "mitochondriacs." However, theadvent, development, andsubsequentdominance ofmoleculargenetics/molecularbiologyandmoleculartechnologyinbiomedical researchwereaccompaniedbythenearlycompletesubmersionofinterestinareas ofintermediarymetabolismandtumorcellmetabolism. Forthepast30orsoyears, graduateandpostgraduatetraining, experienceandfocusinbiochemistry, meta- lism, enzymology, cellphysiologyhavedeclined, beingdisplacedbythedo- nanceofmoleculartechnologies. Therecentrevelationsandadvancesinmolecular genetics/molecularbiologyandthedevelopmentofmolecularandnanotechnology providenewdimensionstoapplytotheunderstandingandelucidationoftheroleof intermediarymetabolismandmitochondrialfunctioninthedevelopmentandp- gressionofcancers. Toaddresstheissuesoftumormetabolism, thepresentand futuregenerationsofresearchersmustintegratetheknowledgeandmethods of biochemistrywiththeknowledgeandtechnologyofmolecularbiology. Thefocusonmitochondriaiscentraltodiscussionsandissuesofintermediary metabolism. Thegenetictransformationofnormalfunctionalcellstoneoplastic cellsimposestheneedforalterationsinintermediarymetabolismandmitochond- alfunctiontoprovidethebioenergetic/synthetic/growthrequirementsforthep- gression of the neoplastic cell to malignancy. In the absence of the metabolic transformation, theneoplasticmalignantcellwillnotachieveitsmalignantpot- tial. Thus, itiscriticaltoestablishtheroleofthemitochondriainthemalignant process. Moreover, speci?calterationsindifferentcancertypesmustbeidenti?ed. Such information will provide new approaches to the treatment and perhaps preventionofdifferingcancers. TheadventofMetabolomicsforthedetectionof v vi Preface cancer and progression of malignancy is dependent upon the elucidation and identi?cationofalteredmetabolismandmitochondrialfunction. Thus, thisexciting journeyincancerresearchhasbarelybegunandhasalongwaytogo. Thisbook, Mitochondria and Cancer, and its subject matter provide a roadmap and the preparationtoproceedonthisjourney. Wearegreatlyindebtedtothecontributingauthorsfortheirenthusiasticsupport andwritingachapterintheirareaofexpertise. WearegratefultoMs. DonnaOvak for secretarial help and our families for their patience and support in putting togetherthisbook. Thisbookisdedicatedtopast, present, andfuture"mitoch- driacs"aroundtheworld. Buffalo, NY KeshavK. Singh Baltimore, MD LeslieC. Costello Contents MitochondriaandCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 KjerstinM. Owens, J. S. Modica-Napolitano, andKeshavK. Singh WarburgandhisLegacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 MichaelRistowandTimJ. Schulz TheLipogenicSwitchinCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 KoenBrusselmansandJohannesV. Swinnen CitrateMetabolisminProstateandOtherCancers . .