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Open Biol. 2013 Watson

Open Biol. 2013 Watson

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, 120144, published online 8 January 2013
Open Biol.
Jim Watson
metastatic cancersOxidants, antioxidants and the current incurability of
any medium, provided the original work is properly cited.Attribution License, which permits unrestricted use, distribution, and reproduction inThis is an open-access article distributed under the terms of the Creative Commons
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(27 articles)molecular biology  (19 articles)genetics  Articles on similar topics can be found in the following collections
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 on January 10, 2013rsob.royalsocietypublishing.orgDownloaded from 
Cite this article:
Watson J. 2013 Oxidants,antioxidants and the current incurability of metastatic cancers. Open Biol 3: 120144.http://dx.doi.org/10.1098/rsob.120144Received: 4 October 2012Accepted: 3 December 2012
Subject Area:
molecular biology/genetics
cancer, reactive oxygen species,metastatic cancer
Author for correspondence:
Jim Watsone-mail:berejka@cshl.edu
Oxidants, antioxidants andthe current incurability of metastatic cancers
Jim Watson
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA
1. Summary
Thevastmajorityofallagentsusedtodirectlykillcancercells(ionizingradiation,mostchemotherapeuticagentsandsometargetedtherapies) workthrougheitherdirectlyorindirectlygeneratingreactiveoxygenspeciesthatblockkeystepsinthecell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors,they almost inevitably possess much-heightened amounts of antioxidantsthat effectively block otherwise highly effective oxidant therapies. Also key to better understanding is why and how the anti-diabetic drug metformin (theworld’s most prescribed pharmaceutical product) preferentially kills oxidant-deficient mesenchymal p53
2 2
cells. A much faster timetable should be adoptedtowards developing more new drugs effective against p53
2 2
cancers.Although the mortality from many cancers, particularly those of haemato-poietic cells, has been steadily falling, the more important statistic may bethat so many epithelial cancers (carcinomas) and effectively all mesenchymalcancers (sarcomas) remain largely incurable. Even though an increasing varietyof intelligently designed, gene-targeted drugs now are in clinical use, they gen-erally only temporarily hold back the fatal ravages of major cancers such asthose of the lung, colon and breast that have become metastatic and gone beyond the reach of the skilled surgeon or radiotherapist. Even though wewill soon have comprehensive views of how most cancers arise and functionat the genetic and biochemical level, their ‘curing’ seems now to manyseasonedscientists an even more daunting objective than when the ‘War on Cancer’ wasstarted by President Nixon in December 1971.Propelling me then, 40 years ago, to turn the Cold Spring Harbor Laboratoryintoamajorsiteforunravellingthegeneticunderpinningsofcancerwasthebelief that once the gene-induced molecular pathways to cancer became known, med-icinal chemists would go on to develop much more effective gene-targeteddrugs. Unlike most early proponents of the ‘War on Cancer’, who thought thatDNA-damaging chemotherapeutic agents would bring real victories in one totwo decades, I thought three if not four more decades of focused researchwouldneedtopassbeforewewouldbeinapositiontogoalloutfortotalvictory[1]. In fact, onlyafter the 1988–2003 Human Genome Project provided theworldwith the highly accurate sequences for three billion human DNA letters has it been possible to begin to approach the true genetic complexity of cancer.
2. Molecular pathways to cancer as revealed throughDNA sequencing
2013 The Authors. Published by the Royal Society under the terms of the Creative Commons AttributionLicense http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the originalauthor and source are credited.
 on January 10, 2013rsob.royalsocietypublishing.orgDownloaded from 
protein components of ‘signal transduction pathways’ thatenable external signals (growth factors) to move from the cellsurface receptors to key promoter–enhancer regions along the24 human chromosomes. There they turn up the expression of genesneededforcellgrowthanddivisionaswellastheevasionof programmed cell death, the latter of which much underliesthe ever-growing resistance of late-stage aggressive cancercells to radio- and chemotherapeutic therapies. Most impor-tantly, there exist multiple molecular pathways that bringaboutcellgrowthandproliferation,eachwiththeirownspecificsurface receptors, cytoplasmic transducers, and promoters andenhancers of gene expression [3].Much potential cross talk exists between these pathways,allowing new DNA mutations to create new pathways tocancer when pre-existing ones are blocked. Already we knowthat the emergence of resistance to the gene
-targetedanti-melanoma drug Zelboraf frequently results from driverpathway cross talk, as does resistance to the targeted drugsIressa and Tarceva when they are deployed against EGFR-driven lung cancers. Given the seemingly almost intrinsicgenetic instability of many late-stage cancers, we should not besurprised when key old timers in cancer genetics doubt beingableto truly cure most victimsof widespread metastaticcancer.Resistance to gene-targeted anti-cancer drugs also comesabout as a consequence of the radical changes in underlyingpatterns of gene expression that accompany the epithelial-to-mesenchymalcelltransitions(EMTs)thatcancercellsundergowhen their surrounding environments become hypoxic [4].EMTs generate free-floating mesenchymal cells whose flexibleshapes and still high ATP-generating potential give them thecapacityforamoeboidcell-likemovementsthatletthemmetasta-size to other body locations (brain,liver,lungs).Only when theyhave so moved do most cancers become truly life-threatening.
3. Epithelial-to-mesenchymal transitionsare a consequence of changes intranscriptional regulation
EMTs leave intact the pre-existing order of DNA bases whilechanging the way they are read into RNA transcripts. Under-lying transcriptional regulation are site-specific DNA-bindingproteins, and sometimes regulatory RNAs, that recruit togenesthemachineryrequiredtoreadthosegenes.Thisincludesthe general transcription machinery and also enzymes thatmodify the histones around which chromosomal DNA iswound, and the DNA itself. These enzymes mediate methyl-ation and acetylation of histones, as well as remodelling of thenucleosomes in various ways, and methylation of DNA bases,changesthatcaninfluencehowagivengeneisexpressed.Regu-lation oftranscription extends far beyond its role in influencinghow cancer cells respond to changes in their environmentalsurroundings. This regulation underlies all the multipleswitches that accompany the transition of fertilized eggs intothe differentiated cells(lung,kidney, etc.)ofmature organisms.
4. IL6-like cytokines drive mesenchymalcells to commence cell proliferation
Much holding back the creation of effective drugs againstmesenchymal cancer cells has long been ignorance of theexternally driven signalling pathways propelling them intostem cell growth and subsequent differentiation. Most atten-tion until now has been focused on the Wnt signallingpathway that sends
-catenin into the cell nucleus to activatethe TCF transcription factor for essential roles in EMTs aswell as stem cell functioning [5,6]. An even more important villain may have been virtually staring in our faces foralmost two decades—one or more of the cytokine mediatorsof inflammation and immunity, in particular, the IL6 interleu-kin. IL6 blood serum levels, for example, steadily go up asincurable cancers become more life-threatening [7,8]. Auto- crine loops probably exist where cytokine binding to theirrespective cell surface receptors sets into motion downstreamgene-activating pathways that not only generate more IL6molecules but give their respective cancer cells an aura of almost true immortality by blocking the major pathway toprogrammed cell death (apoptosis).
Pushing by cytokines of otherwise quiescent mesenchymal cancer cells to grow and divideprobably explains why anti-inflammatory agents such as aspirinlead to much less cancer in those human beings who regularlytake them
[9].Unfortunately, the inherently very large number of pro-teins whose expression goes either up or down as themesenchymal cancer cells move out of quiescent states intothe cell cycle makes it still very tricky to know, beyond thecytokines, what other driver proteins to focus on for drugdevelopment. Ideally, we should largely focus first on findinginhibitorsofcancercellproliferationasopposedtoinhibitorsof cancercellgrowth.Inhibiting,say,thesynthesisofcellularmol-ecularbuildingblockswillslowdownnotonlythemetabolismofcancercellsbutalsothat of our body’snormallyfunctioningcells. By contrast, blocking proteins specifically movingthroughthecellcycleshouldleaveuntouchedthenormalfunc-tioning of the vast majority of our body’s cells and so generatemuch less unwanted side effects.
5. The gene transcription activatorMyc allows cells to move throughthe cell cycle
Long thought to be a key, if not
key, protein against whichto develop cell-proliferation-inhibiting drugs is the powerfulgene transcription activator Myc. First known for its role indriving cancers of blood-forming lymphocytes (e.g. Burkitt’slymphoma), Myc now also has been found to be a key driverof the rapidly fatal ‘small cell’ lung cancers as well as thelikely driver of many late-stage incurable cancers, includingreceptor negative and ductal breast cancers.
Lots of Myc mayturn out to be an essential feature of much of the truly incurablecancer
. It simultaneously turns up the synthesis of the morethan 1000 different proteins required to move all cellsthroughthe cell cycle. Although precisely how this almost 400-aminoacid long polypeptide works at the molecular level remains to be worked out, it seems to play a unique role that cannot behandled by anyother class of transcription factors. Unlike ourfirst hunch that Myc was somehow an on–off specifier of gene activity, it is a nonlinear amplifier of expression actinguniversally on active genes except for the immediate earlygenes that become expressed before
[10,11]. Already many serious efforts have been made to develop drugs that
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