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 .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 .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
.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
many serious efforts have been made to develop drugs that
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