daw
08-23-2005, 12:23 PM
From American Journal of Clinical Pathology
Overexpression of Decoy Receptor 3 in Precancerous Lesions and Adenocarcinoma of the Esophagus
Posted 08/12/2005
Huixiang Li, MD, PhD; Lurong Zhang, MD, PhD; Hong Lou, MD; Ivan Ding, MD; Sunghee Kim, PhD; Luping Wang, MD; Jiaoti Huang, MD, PhD; P. Anthony Di Sant'Agnese, MD; Jun-Yi Lei, MD, PhD
Abstract
Overexpression of decoy receptor (DcR) 3 protein, a recently discovered member of the tumor necrosis factor receptor superfamily, was examined in 40 esophagogastrectomy specimens containing areas of Barrett esophagus (n = 27), low-grade dysplasia (n = 27), high-grade dysplasia or carcinoma in situ (n = 22), and esophageal adenocarcinoma (EAC; n = 28) with immunohistochemical analysis. The results revealed significantly more overexpression of DcR3 in high-grade dysplasia or carcinoma in situ and EAC than in benign esophageal mucosa (both P < .0001), Barrett esophagus (both P < .001), and low-grade dysplasia (P < .01 and P = .033, respectively). Low-grade dysplasia also showed significant overexpression of DcR3 compared with benign esophagus (P < .05) but not with Barrett esophagus (P > .05). DcR3 overexpression seems to negatively correlate with the grade of EAC. Our results suggest that overexpression of DcR3 protein might aid in the diagnosis of high-grade dysplasia or carcinoma in situ and EAC and also might serve as a potential therapeutic target.
Introduction
Esophageal adenocarcinoma (EAC) is becoming more common worldwide, with its incidence tripling in the United States from 1976 to 1990 and an annual increase of approximately 10%.[1] More than 13,900 new cases with 13,000 deaths were anticipated in the United States in 2003.[2] Barrett esophagus is considered a key precancerous lesion with a strong association with the development of dysplasia and subsequent EAC,[3] but the pathogenic mechanisms of this process remain unclear.
Decoy receptor (DcR) 3 is a recently discovered member of the tumor necrosis factor receptor superfamily, which had 23 groupings and 30 members as of May 2005.[4] The DcR group consists of 4 members, DcR1, DcR2, and DcR3 and osteoprotegerin.[5,6] Although osteoprotegerin has very low physiologic affinity for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), DcR1 and DcR2 are capable of binding TRAIL but incapable of transducing the death signal because of lack of a death domain in their structures.[6,7] In fact, DcR1 and DcR2 compete with the TRAIL receptor for the li-gands and subsequently inhibit apoptosis. In addition, DcR can inhibit T-cell activation via the repression of actin polymerization and pseudopodium formation by T cells.[8]
DcR3 is a unique member in the DcR group because it is secreted rather than membrane-bound like DcR1 and DcR2. In addition, DcR3 binds to the Fas ligand, not the TRAIL, as other DcRs do.[9] DcR3 also can modulate immune cell interaction by down-regulating the functions of macrophages and T cells.[8,10] DcR's functions of blocking apoptosis and escaping immune surveillance are important in carcinogenesis. The gene amplification and overexpression of DcR3 messenger RNA (mRNA) and protein have been demonstrated in lymphoma, glioblastoma, and cancer of the lung, esophagus, colon, and pancreas.[9,11-14] The serum level of DcR3 also was significantly elevated in 56.2% of a variety of tumors, including cancers of the digestive system, thyroid, lung, and breast.[15] In the present study, we examined the expression of DcR3 in 40 cases of Barrett esophagus-associated lesions by immunohistochemical analysis. Association of DcR3 overexpression with the pathogenesis of EAC and the potential application of DcR3 overexpression in the diagnosis and treatment of EAC also are discussed.
complete article: http://www.medscape.com/viewarticle/510153?src=mp
Overexpression of Decoy Receptor 3 in Precancerous Lesions and Adenocarcinoma of the Esophagus
Posted 08/12/2005
Huixiang Li, MD, PhD; Lurong Zhang, MD, PhD; Hong Lou, MD; Ivan Ding, MD; Sunghee Kim, PhD; Luping Wang, MD; Jiaoti Huang, MD, PhD; P. Anthony Di Sant'Agnese, MD; Jun-Yi Lei, MD, PhD
Abstract
Overexpression of decoy receptor (DcR) 3 protein, a recently discovered member of the tumor necrosis factor receptor superfamily, was examined in 40 esophagogastrectomy specimens containing areas of Barrett esophagus (n = 27), low-grade dysplasia (n = 27), high-grade dysplasia or carcinoma in situ (n = 22), and esophageal adenocarcinoma (EAC; n = 28) with immunohistochemical analysis. The results revealed significantly more overexpression of DcR3 in high-grade dysplasia or carcinoma in situ and EAC than in benign esophageal mucosa (both P < .0001), Barrett esophagus (both P < .001), and low-grade dysplasia (P < .01 and P = .033, respectively). Low-grade dysplasia also showed significant overexpression of DcR3 compared with benign esophagus (P < .05) but not with Barrett esophagus (P > .05). DcR3 overexpression seems to negatively correlate with the grade of EAC. Our results suggest that overexpression of DcR3 protein might aid in the diagnosis of high-grade dysplasia or carcinoma in situ and EAC and also might serve as a potential therapeutic target.
Introduction
Esophageal adenocarcinoma (EAC) is becoming more common worldwide, with its incidence tripling in the United States from 1976 to 1990 and an annual increase of approximately 10%.[1] More than 13,900 new cases with 13,000 deaths were anticipated in the United States in 2003.[2] Barrett esophagus is considered a key precancerous lesion with a strong association with the development of dysplasia and subsequent EAC,[3] but the pathogenic mechanisms of this process remain unclear.
Decoy receptor (DcR) 3 is a recently discovered member of the tumor necrosis factor receptor superfamily, which had 23 groupings and 30 members as of May 2005.[4] The DcR group consists of 4 members, DcR1, DcR2, and DcR3 and osteoprotegerin.[5,6] Although osteoprotegerin has very low physiologic affinity for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), DcR1 and DcR2 are capable of binding TRAIL but incapable of transducing the death signal because of lack of a death domain in their structures.[6,7] In fact, DcR1 and DcR2 compete with the TRAIL receptor for the li-gands and subsequently inhibit apoptosis. In addition, DcR can inhibit T-cell activation via the repression of actin polymerization and pseudopodium formation by T cells.[8]
DcR3 is a unique member in the DcR group because it is secreted rather than membrane-bound like DcR1 and DcR2. In addition, DcR3 binds to the Fas ligand, not the TRAIL, as other DcRs do.[9] DcR3 also can modulate immune cell interaction by down-regulating the functions of macrophages and T cells.[8,10] DcR's functions of blocking apoptosis and escaping immune surveillance are important in carcinogenesis. The gene amplification and overexpression of DcR3 messenger RNA (mRNA) and protein have been demonstrated in lymphoma, glioblastoma, and cancer of the lung, esophagus, colon, and pancreas.[9,11-14] The serum level of DcR3 also was significantly elevated in 56.2% of a variety of tumors, including cancers of the digestive system, thyroid, lung, and breast.[15] In the present study, we examined the expression of DcR3 in 40 cases of Barrett esophagus-associated lesions by immunohistochemical analysis. Association of DcR3 overexpression with the pathogenesis of EAC and the potential application of DcR3 overexpression in the diagnosis and treatment of EAC also are discussed.
complete article: http://www.medscape.com/viewarticle/510153?src=mp