Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer

Kawamata,Futoshi; Kamachi,Hirofumi; Einama,Takahiro; Homma,Shigenori; Tahara,Munenori; Miyazaki,Masaya; Tanaka,Shinya; Kamiyama,Toshiya; Nishihara,Hiroshi; Taketomi,Akinobu; Todo,Satoru

doi:10.3892/ijo.2012.1662

Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer

Authors:
- Futoshi Kawamata
- Hirofumi Kamachi
- Takahiro Einama
- Shigenori Homma
- Munenori Tahara
- Masaya Miyazaki
- Shinya Tanaka
- Toshiya Kamiyama
- Hiroshi Nishihara
- Akinobu Taketomi
- Satoru Todo
View Affiliations

Affiliations: Department of General Surgery, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, Department of Cancer Pathology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, Department of Translational Pathology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
Published online on: October 15, 2012 https://doi.org/10.3892/ijo.2012.1662
Pages: 2109-2118

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mesothelin is expressed in various types of malignant tumors, and we recently reported that the expression of mesothelin was related to unfavorable patient outcome in pancreatic ductal adenocarcinoma and gastric adenocarcinoma. In this study, we examined the clinicopathological significance of mesothelin expression in extrahepatic bile duct cancer (EHBDCA), especially in terms of its association with the staining pattern. Tissue samples from 61 EHBDCA (16 hilar cholangiocarcinoma, 17 upper bile duct adenocarcinoma, 20 middle bile duct adenocarcinoma and 8 distal bile duct adenocarcinoma) were immunohistochemically examined. The expression levels of mesothelin in tumor cells was classified into the localization of mesothelin in luminal membrane and/or cytoplasm, in addition to high and low according to the staining intensity and proportion as a conventional analysis. ‘High-level expression’ of mesothelin (47.5%) was statistically correlated with liver metastasis (P=0.013) and poorer patient outcome (P=0.022), while ‘luminal membrane positive’ of mesothelin (52.5%) was more significantly correlated with liver metastasis (P=0.006), peritoneal metastasis (P=0.024) and unfavorable patient outcome (P=0.017). Moreover, we found that ‘cytoplasmic expression’ isolated from ‘luminal membrane negative’ of mesothelin represented the best patient prognosis throughout this study. We describe the expression pattern level of mesothelin, i.e., in luminal membrane or cytoplasm both high and low level, evidently indicate the patient prognosis of EHBDCA, suggesting the pivotal role of mesothelin in cancer promotion depending on its intracellular localization.

View Figures

View References

1.	Ito K, Ito H, Allen PJ, et al: Adequate lymph node assessment for extrahepatic bile duct adenocarcinoma. Ann Surg. 251:675–681. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Ohashi M, Kusumi T, Sato F, et al: Expression of syndecan-1 and E-cadherin is inversely correlated with poor patient’s prognosis and recurrent status of extrahepatic bile duct carcinoma. Biomed Res. 30:79–86. 2009.PubMed/NCBI
3.	Jarnagin WR, Fong Y, DeMatteo RP, et al: Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 234:507–519. 2001. View Article : Google Scholar : PubMed/NCBI
4.	Akoad M and Jenkins R: Proximal biliary malignancy. Surg Clin North Am. 88:1409–1428. x–xi. 2008. View Article : Google Scholar : PubMed/NCBI
5.	Veillette G and Castillo CF: Distal biliary malignancy. Surg Clin North Am. 88:1429–1447. xi2008. View Article : Google Scholar : PubMed/NCBI
6.	Chang K and Pastan I: Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA. 93:136–140. 1996. View Article : Google Scholar : PubMed/NCBI
7.	Chang K, Pastan I and Willingham MC: Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer. 50:373–381. 1992. View Article : Google Scholar : PubMed/NCBI
8.	Argani P, Iacobuzio-Donahue C, Ryu B, et al: Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 7:3862–3868. 2001.PubMed/NCBI
9.	Hassan R, Kreitman RJ, Pastan I and Willingham MC: Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 13:243–247. 2005. View Article : Google Scholar : PubMed/NCBI
10.	Ordonez NG: Value of mesothelin immunostaining in the diagnosis of mesothelioma. Mod Pathol. 16:192–197. 2003. View Article : Google Scholar : PubMed/NCBI
11.	Ordonez NG: Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 27:1418–1428. 2003. View Article : Google Scholar : PubMed/NCBI
12.	Einama T, Kamachi H, Nishihara H, et al: Co-Expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma. Pancreas. 40:1276–1282. 2011. View Article : Google Scholar : PubMed/NCBI
13.	Hassan R, Bera T and Pastan I: Mesothelin: a new target for immunotherapy. Clin Cancer Res. 10:3937–3942. 2004. View Article : Google Scholar : PubMed/NCBI
14.	Li M, Bharadwaj U, Zhang R, et al: Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. Mol Cancer Ther. 7:286–296. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Cheng WF, Huang CY, Chang MC, et al: High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. Br J Cancer. 100:1144–1153. 2009. View Article : Google Scholar : PubMed/NCBI
16.	Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R and Brackett D: Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 124:838–845. 2005. View Article : Google Scholar : PubMed/NCBI
17.	Swierczynski SL, Maitra A, Abraham SC, et al: Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. Hum Pathol. 35:357–366. 2004. View Article : Google Scholar : PubMed/NCBI
18.	Baba K, Ishigami S, Arigami T, et al: Mesothelin expression correlates with prolonged patient survival in gastric cancer. J Surg Oncol. 105:195–199. 2012. View Article : Google Scholar : PubMed/NCBI
19.	Einama T, Homma S, Kamachi H, et al: Luminal membrane expression of mesothelin is a prominent poor prognostic factor for gastric cancer. Br J Cancer. 107:137–142. 2012. View Article : Google Scholar : PubMed/NCBI
20.	Zhao H, Davydova L, Mandich D, Cartun RW and Ligato S: S100A4 protein and mesothelin expression in dysplasia and carcinoma of the extrahepatic bile duct. Am J Clin Pathol. 127:374–379. 2007. View Article : Google Scholar : PubMed/NCBI
21.	Sobin LH and Wittekind CW: TNM Classification of Malignant Tumors. 6th edition. Wiley-Liss; New York: 2002
22.	Inami K, Kajino K, Abe M, et al: Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma. Oncol Rep. 20:1375–1380. 2008.PubMed/NCBI
23.	Shimizu A, Hirono S, Tani M, et al: Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma. Cancer Sci. 103:739–746. 2012. View Article : Google Scholar : PubMed/NCBI
24.	Bharadwaj U, Marin-Muller C, Li M, Chen C and Yao Q: Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis. 32:1013–1024. 2011. View Article : Google Scholar
25.	Bharadwaj U, Marin-Muller C, Li M, Chen C and Yao Q: Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression. Mol Cancer. 10:1062011.PubMed/NCBI
26.	Chang MC, Chen CA, Hsieh CY, et al: Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 424:449–458. 2009. View Article : Google Scholar : PubMed/NCBI
27.	Hassan R, Schweizer C, Lu KF, et al: Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: implications for cancer therapy. Lung Cancer. 68:455–459. 2010. View Article : Google Scholar : PubMed/NCBI
28.	Bharadwaj U, Li M, Chen C and Yao Q: Mesothelin-induced pancreatic cancer cell proliferation involves alteration of cyclin E via activation of signal transducer and activator of transcription protein 3. Mol Cancer Res. 6:1755–1765. 2008. View Article : Google Scholar
29.	Inami K, Abe M, Takeda K, et al: Antitumor activity of anti-CERC/mesothelin monoclonal antibody in vivo. Cancer Sci. 101:969–974. 2009. View Article : Google Scholar : PubMed/NCBI
30.	Yen MJ, Hsu CY, Mao TL, et al: Diffuse mesothelin expression correlates with prolonged patient survival in ovarian serous carcinoma. Clin Cancer Res. 12:827–831. 2006. View Article : Google Scholar : PubMed/NCBI
31.	Hudis CA: Trastuzumab - mechanism of action and use in clinical practice. N Engl J Med. 357:39–51. 2007. View Article : Google Scholar : PubMed/NCBI
32.	Huang TW, Wang CH and Hsieh CB: Effects of the anti-epidermal growth factor receptor antibody cetuximab on cholangiocarcinoma of the liver. Onkologie. 30:129–131. 2007. View Article : Google Scholar : PubMed/NCBI
33.	Sprinzl MF, Schimanski CC, Moehler M, Schadmand-Fischer S, Galle PR and Kanzler S: Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report. BMC Cancer. 6:1902006. View Article : Google Scholar : PubMed/NCBI
34.	Bralet MP, Bellin MF, Guettier C, Adam R and Paule B: Response to cetuximab and gemcitabine-oxaliplatin in an advanced case of intrahepatic cholangiocarcinoma. Clin Oncol (R Coll Radiol). 18:4262006. View Article : Google Scholar : PubMed/NCBI
35.	Kreitman RJ, Hassan R, Fitzgerald DJ and Pastan I: Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res. 15:5274–5279. 2009. View Article : Google Scholar : PubMed/NCBI
36.	Hassan R, Cohen SJ, Phillips M, et al: Phase I clinical trial of the Chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin expressing cancers. Clin Cancer Res. 16:6132–6138. 2010. View Article : Google Scholar : PubMed/NCBI
37.	Hassan R, Bullock S, Premkumar A, et al: Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 13:5144–5149. 2007. View Article : Google Scholar : PubMed/NCBI
38.	Hassan R, Ebel W, Routhier EL, et al: Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 7:202007.PubMed/NCBI