BACKGROUND: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.
BACKGROUND: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS:Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.
Authors: Tshering D Lama-Sherpa; Shamik Das; Dominique C Hinshaw; Sarah C Kammerud; Patrick N Song; Heba A Alsheikh; Anna G Sorace; Rajeev S Samant; Lalita A Shevde Journal: Mol Cancer Res Date: 2021-09-30 Impact factor: 6.333
Authors: Ronan J Kelly; Amir M Ansari; Tomoharu Miyashita; Marianna Zahurak; Frank Lay; A Karim Ahmed; Louis J Born; Maryam K Pezhouh; Kevan J Salimian; Christopher Ng; Aerielle E Matsangos; Anne-Heloise Stricker-Krongrad; Ken-Ichi Mukaisho; Guy P Marti; Christine H Chung; Marcia I Canto; Michelle A Rudek; Stephen J Meltzer; John W Harmon Journal: Ann Surg Date: 2021-06-01 Impact factor: 13.787
Authors: Ali H Zaidi; Lindsey T Saldin; Lori A Kelly; Linda Bergal; Ricardo Londono; Juliann E Kosovec; Yoshihiro Komatsu; Pashtoon M Kasi; Amit A Shetty; Timothy J Keane; Shyam J Thakkar; Luai Huleihel; Rodney J Landreneau; Stephen F Badylak; Blair A Jobe Journal: PLoS One Date: 2015-03-31 Impact factor: 3.240
Authors: Juliann E Kosovec; Ali H Zaidi; Yoshihiro Komatsu; Pashtoon M Kasi; Kyle Cothron; Diane V Thompson; Edward Lynch; Blair A Jobe Journal: PLoS One Date: 2014-04-04 Impact factor: 3.240
Authors: Ali H Zaidi; Lori A Kelly; Rachael E Kreft; Mark Barlek; Ashten N Omstead; Daisuke Matsui; Natalie H Boyd; Kathryn E Gazarik; Megan I Heit; Laura Nistico; Pashtoon M Kasi; Tracy L Spirk; Barbara Byers; Emily J Lloyd; Rodney J Landreneau; Blair A Jobe Journal: BMC Cancer Date: 2016-02-02 Impact factor: 4.430
Authors: Juliann E Kosovec; Ali H Zaidi; Ashten N Omstead; Daisuke Matsui; Mark J Biedka; Erin J Cox; Patrick T Campbell; Robert W W Biederman; Ronan J Kelly; Blair A Jobe Journal: Oncotarget Date: 2017-11-01