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Zombie cancer cells eat themselves to live

April 6, 2014
Courtesy of University of Colorado Denver
and World Science staff

A pro­cess in which cells “eat” parts of them­selves in times of stress may al­low can­cer cells to re­cov­er and di­vide rath­er than die when faced with chemoth­er­a­pies, new re­search finds.

Sci­en­tists are hop­ing to ex­ploit the knowl­edge to de­vel­op ther­a­pies that un­der­mine this es­cape rou­tine by ma­lig­nant cells.

The Uni­vers­ity of Col­o­rad­o Can­cer Cen­ter study is pub­lished in the jour­nal Cell Re­ports and was pre­sented April 5 at the an­nu­al con­fer­ence of the Amer­i­can As­socia­t­ion for Can­cer Re­search in San Die­go. 

Cells can un­dergo a pro­cess called au­to­pha­gy, from the Greek “to eat one­self.” It’s a pro­cess of cel­lu­lar re­cy­cling in which cel­lu­lar com­part­ments called au­to­pha­go­somes en­cap­su­late ex­tra or dan­ger­ous ma­te­ri­al and car­ry it to com­part­ments known as lyso­somes for dis­pos­al. 

Like tear­ing apart a Lego kit, au­to­pha­gy breaks down un­needed cel­lu­lar com­po­nents in­to build­ing blocks of en­er­gy or pro­teins. This can be use­ful in sur­viv­ing times of low en­er­gy or stay­ing safe from poi­sons and pathogens, among oth­er situ­a­tions.

“What we showed is that if this mech­an­ism does­n’t work right, for ex­am­ple if au­to­pha­gy is too high or if the tar­get reg­u­lat­ed by au­to­pha­gy is­n’t around, can­cer cells may be able to res­cue them­selves from death caused by chemoth­er­a­pies,” said An­drew Thor­burn, dep­u­ty di­rec­tor of the Uni­vers­ity of Col­o­rad­o Can­cer Cen­ter.

A mov­ie ac­com­pa­nying the study on­line shows a can­cer cell dy­ing. In the first few frames, struc­tures in the cell break down and cel­lu­lar com­part­ments called mi­to­chon­dria re­lease pro­teins in a pro­cess ab­bre­vi­at­e as MOMP, con­sid­ered a com­mon mark­er of cell death. But then high au­to­pha­gy al­lows the cell to en­cap­su­late and “di­gest” these re­leased pro­teins be­fore the pro­cess can keep the cell well and truly dead. The can­cer cell re­cov­ers and goes on to di­vide.

“The im­plica­t­ion here is that if you in­hib­it au­to­pha­gy you’d make this less likely to hap­pen, i.e. when you kill can­cer cells they would stay dead,” Thor­burn said. Thor­burn and col­leagues in­clud­ing post­doc­tor­al re­searcher Ja­cob Gump also found that au­to­pha­gy de­pends on a tar­get mol­e­cule called PU­MA to reg­u­late cell death.

The find­ing has im­por­tant im­plica­t­ions, Thor­burn said. First, it shows a mech­an­ism whe­reby au­to­pha­gy con­trols cell death. Sec­ond, the study fur­ther re­in­forces the clin­i­cal po­ten­tial of in­hib­iting au­to­pha­gy to sen­si­tize can­cer cells to chemoth­erapy.

“Au­tophagy is com­plex and as yet not fully un­der­stood,” Thor­burn said. “But now that we see a mo­lec­u­lar mech­an­ism whe­reby cell-fate can be de­ter­mined by au­to­pha­gy, we hope to dis­cov­er pa­tient popula­t­ions that could ben­e­fit from drugs that in­hib­it this ac­tion.”


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A process in which cells “eat” parts of themselves in times of stress may allow cancer cells to recover and divide rather than die when faced with chemotherapies, new research finds. Scientists are hoping to exploit the knowledge to develop therapies that undermine this escape routine by malignant cells. The University of Colorado Cancer Center study is published in the journal Cell Reports and was presented April 5 at the annual conference of the American Association for Cancer Research in San Diego. Cells can undergo a process called autophagy, from the Greek “to eat oneself.” It’s a process of cellular recycling in which cellular compartments called autophagosomes encapsulate extra or dangerous material and carry it to compartments known as lysosomes for disposal. Like tearing apart a Lego kit, autophagy breaks down unneeded cellular components into building blocks of energy or proteins for use in surviving times of low energy or staying safe from poisons and pathogens, among other uses. “What we showed is that if this mechanism doesn’t work right, for example if autophagy is too high or if the target regulated by autophagy isn’t around, cancer cells may be able to rescue themselves from death caused by chemotherapies,” said Andrew Thorburn, deputy director of the University of Colorado Cancer Center. A movie accompanying the study online shows a cancer cell dying. In the first few frames, structures in the cell break down and cellular compartments called mitochondria release proteins in a process abbreviated as MOMP, considered a common marker of cell death. But then high autophagy allows the cell to encapsulate and “digest” these released proteins before the process can keep the cell well and truly dead. The cancer cell recovers and goes on to divide. “The implication here is that if you inhibit autophagy you’d make this less likely to happen, i.e. when you kill cancer cells they would stay dead,” Thorburn said. Thorburn and colleagues including postdoctoral researcher Jacob Gump found that autophagy depends on a target molecule called PUMA to regulate cell death. When PUMA is absent, it doesn’t matter if autophagy is inhibited because without the communicating action of PUMA, cancer cells continue to live. The finding has important implications, he said. First, it shows a mechanism whereby autophagy controls cell death. Second, the study further reinforces the clinical potential of inhibiting autophagy to sensitize cancer cells to chemotherapy. “Autophagy is complex and as yet not fully understood,” Thorburn said. “But now that we see a molecular mechanism whereby cell-fate can be determined by autophagy, we hope to discover patient populations that could benefit from drugs that inhibit this action.”