Esophageal Can­cer

New Un­der­stand­ing of Fastest-Ris­ing Solid Tu­mor in U.S.

Wellness Update - - Esophageal Cancer -

Re­searchers at Columbia Univer­sity Med­i­cal Cen­ter (CUMC) have iden­ti­fied the crit­i­cal early cel­lu­lar and molec­u­lar events that give rise to a type of esophageal can­cer called esophageal ade­no­car­ci­noma, the fastest-ris­ing solid tu­mor in the United States. The find­ings, pub­lished on­line in Can­cer Cell (21(1) 36–51 (2012), chal­lenge con­ven­tional wis­dom re­gard­ing the ori­gin and devel­op­ment of this deadly can­cer and its pre­cur­sor le­sion, Bar­rett’s esoph­a­gus, and high­light pos­si­ble tar­gets for new clin­i­cal ther­a­pies.

Lack­ing a good an­i­mal model of esophageal ade­no­car­ci­noma (EAC), re­searchers have been hard pressed to ex­plain ex­actly where and how this can­cer arises. What is known is that EAC is usu­ally trig­gered by gas­troe­sophageal re­flux disease (GERD), in which bile acid and other stom­ach con­tents leak back­wards from the stom­ach to the esoph­a­gus, the mus­cu­lar tube that moves food from the mouth to the stom­ach. Over time, acid re­flux can ir­ri­tate and in­flame the esoph­a­gus, lead­ing to Bar­rett’s esoph­a­gus, an asymp­to­matic pre­can­cer­ous con­di­tion in which the tis­sue lin­ing the esoph­a­gus is re­placed by tis­sue sim­i­lar to the lin­ing of the in­tes­tine. A small num­ber of peo­ple with Bar­rett’s esoph­a­gus even­tu­ally go on to de­velop EAC.

Us­ing a new ge­net­i­cally en­gi­neered mouse model of esophagi­tis, the CUMC re­searchers have clar­i­fied crit­i­cal cel­lu­lar and molec­u­lar changes that oc­cur dur­ing the devel­op­ment of Bar­rett’s esoph­a­gus and EAC. In hu­man pa­tients, acid re­flux of­ten leads to over­ex­pres­sion of a mol­e­cule called in­ter­leukin-1 beta, an im­por­tant me­di­a­tor of the in­flam­ma­tory re­sponse, re­ported study leader Ti­mothy C. Wang, MD, the Dorothy L. and Daniel H. Sil­ber­berg Pro­fes­sor of Medicine at CUMC. Thus, Wang and his col­leagues cre­ated a trans­genic mouse in which in­ter­leukin-1 beta was over­ex­pressed in the esoph­a­gus.

Over­ex­pres­sion of in­ter­leukin-1 beta in the mouse esoph­a­gus re­sulted in chronic esophageal in­flam­ma­tion (esophagi­tis) and ex­pan­sion of pro­gen­i­tor cells that were sus­tained by the notch sig­nal­ing path­way. Notch is a fun­da­men­tal sig­nal­ing sys­tem used by neigh­bor­ing cells to com­mu­ni­cate with each other in or­der to as­sume their proper devel­op­men­tal role. “When we in­hib­ited notch sig­nal­ing, that blocked pro­lif­er­a­tion and sur­vival of the pre-ma­lig­nant cells, so that’s a new pos­si­ble clin­i­cal strat­egy to use in Bar­rett’s pa­tients at high risk for can­cer devel­op­ment,” noted Dr. Wang.

For decades, in­ves­ti­ga­tors thought that the phys­i­o­log­i­cal changes as­so­ci­ated with Bar­rett’s esoph­a­gus orig­i­nate in the lower esoph­a­gus. “How­ever, our study shows that Bar­rett’s esoph­a­gus ac­tu­ally arises in the gas­tric car­dia, a small re­gion be­tween the lower part of the esoph­a­gus and the up­per, acid-se­cret­ing por­tion of the stom­ach,” said Dr. Wang. “What hap­pens is that the bile acid and in­flam­ma­tory cy­tokines ac­ti­vate stem cells at this tran­si­tion zone, and they be­gin mi­grat­ing up to­ward the esoph­a­gus, where they take on this in­testi­nal-like ap­pear­ance.”

The re­searchers also demon­strated that th­ese changes oc­cur pri­mar­ily in colum­nar-like ep­ithe­lial cells, rather than in goblet cells, as was pre­vi­ously thought.

“All told, the find­ings present a new model for the patho­gen­e­sis of Bar­rett’s esoph­a­gus and esophageal ade­no­car­ci­noma,” said Dr. Wang.

Bar­rett’s esoph­a­gus af­fects about 1 per­cent of adults in the United States. Men are af­fected by Bar­rett’s esoph­a­gus twice as fre­quently as women, and Cau­casian men are af­fected more fre­quently than men of other races. The av­er­age age at di­ag­no­sis is 50. At present, there is no way to de­ter­mine which pa­tients with the con­di­tion will de­velop EAC. EAC is in­creas­ing in in­ci­dence about 7 to 8 per­cent a year, mak­ing it the most rapidly ris­ing solid tu­mor in the U.S.

Treat­ment with acid-re­duc­ing drugs can lessen symp­toms of GERD and lower the chances of de­vel­op­ing Bar­rett’s esoph­a­gus and EAC. Low-grade EAC is highly treat­able with en­do­scopic ra­diofre­quency ab­la­tion, pho­to­dy­namic ther­apy, or sur­gi­cal re­sec­tion. Pa­tients with se­vere disease may re­quire open surgery, in which most of the esoph­a­gus is re­moved. The over­all five-year sur­vival rate with ad­vanced disease is about 25 per­cent. -This in­for­ma­tion pro­vided courtesy of Columbia Univer­sity Med­i­cal Cen­ter

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