Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer

Inoue,Satoshi; Tsunoda,Takumi; Riku,Miho; Ito,Hideaki; Inoko,Akihito; Murakami,Hideki; Ebi,Masahide; Ogasawara,Naotaka; Pastan,Ira; Kasugai,Kunio; Kasai,Kenji; Ikeda,Hiroshi; Inaguma,Shingo

doi:10.3892/ol.2020.11290

Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer

Authors:
- Satoshi Inoue
- Takumi Tsunoda
- Miho Riku
- Hideaki Ito
- Akihito Inoko
- Hideki Murakami
- Masahide Ebi
- Naotaka Ogasawara
- Ira Pastan
- Kunio Kasugai
- Kenji Kasai
- Hiroshi Ikeda
- Shingo Inaguma
View Affiliations

Affiliations: Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480‑1195, Japan, Department of Pathology, Aichi Medical University School of Medicine, Nagakute 480‑1195, Japan, Aichi Medical University School of Medicine, Nagakute 480‑1195, Japan, Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA
Published online on: January 10, 2020 https://doi.org/10.3892/ol.2020.11290
Pages: 1741-1750
Copyright: © Inoue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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 (MSLN) is a glycophosphatidylinositol (GPI)‑linked cell surface protein that is highly expressed in several types of malignant tumor, including malignant pleural mesothelioma, ovarian cancer and pancreatic adenocarcinoma. Recently, a comprehensive immunohistochemical study using MN‑1 monoclonal antibody identified a significant number of colorectal tumors in which MSLN was expressed. However, the clinicopathological profiles and survival of patients with MSLN‑positive colorectal cancer have not been fully analyzed. In the current study, the expression of MSLN in 270 primary and 44 metastatic colorectal tumors was immunohistochemically analyzed to determine the clinical usefulness of MSLN immunohistochemistry and to identify potential candidates for future anti‑MSLN therapy. In vitro experiments using colon cancer cell lines were performed to investigate the biological significance of MSLN expression in tumors. The results of univariate analyses identified a significant correlation between MSLN expression and females (P=0.0042). Furthermore, an inverse correlation between MSLN expression and solid/sheet‑like proliferation (P=0.014) was also revealed. Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018). Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04‑4.91; P=0.039) as a potential risk factor. When comparing primary CRCs and the metastasis of each, a weakly positive correlation was identified for MSLN positivity (% positive cells; R=0.484; P<0.0001). The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation. Thus, MSLN immunohistochemistry may be useful in the prognostication of patients with CRC. The results demonstrated that significant numbers of patients with MSLN‑positive CRC exhibiting metastasis could be targeted by anti‑MSLN therapies.

View Figures

View References

1	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
2	Bera TK and Pastan I: Mesothelin is not required for normal mouse development or reproduction. Mol Cell Biol. 20:2902–2906. 2000. View Article : Google Scholar : PubMed/NCBI
3	Chang K, Pai LH, Pass H, Pogrebniak HW, Tsao MS, Pastan I and Willingham MC: Monoclonal antibody K1 reacts with epithelial mesothelioma but not with lung adenocarcinoma. Am J Surg Pathol. 16:259–268. 1992. View Article : Google Scholar : PubMed/NCBI
4	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
5	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
6	Miettinen M and Sarlomo-Rikala M: Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: An immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura. Am J Surg Pathol. 27:150–158. 2003. View Article : Google Scholar : PubMed/NCBI
7	Ordonez NG: Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 27:1418–1428. 2003. View Article : Google Scholar : PubMed/NCBI
8	Kachala SS, Bograd AJ, Villena-Vargas J, Suzuki K, Servais EL, Kadota K, Chou J, Sima CS, Vertes E, Rusch VW, et al: Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin Cancer Res. 20:1020–1028. 2014. View Article : Google Scholar : PubMed/NCBI
9	Thomas A, Chen Y, Steinberg SM, Luo J, Pack S, Raffeld M, Abdullaev Z, Alewine C, Rajan A, Giaccone G, et al: High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget. 6:11694–11703. 2015. View Article : Google Scholar : PubMed/NCBI
10	Einama T, Homma S, Kamachi H, Kawamata F, Takahashi K, Takahashi N, Taniguchi M, Kamiyama T, Furukawa H, Matsuno Y, 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
11	Inaguma S, Wang Z, Lasota J, Onda M, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, et al: Comprehensive immunohistochemical study of mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma. Oncotarget. 8:26744–26754. 2017. View Article : Google Scholar : PubMed/NCBI
12	Li YR, Xian RR, Ziober A, Conejo-Garcia J, Perales-Puchalt A, June CH, Zhang PJ and Tchou J: Mesothelin expression is associated with poor outcomes in breast cancer. Breast Cancer Res Treat. 147:675–684. 2014. View Article : Google Scholar : PubMed/NCBI
13	Thomas A, Chen Y, Berman A, Schrump DS, Giaccone G, Pastan I, Venzon DJ, Liewehr DJ, Steinberg SM, Miettinen M, et al: Expression of mesothelin in thymic carcinoma and its potential therapeutic significance. Lung Cancer. 101:104–110. 2016. View Article : Google Scholar : PubMed/NCBI
14	Yen MJ, Hsu CY, Mao TL, Wu TC, Roden R, Wang TL and Shih IeM: 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
15	Kawamata F, Homma S, Kamachi H, Einama T, Kato Y, Tsuda M, Tanaka S, Maeda M, Kajino K, Hino O, et al: C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma. J Gastroenterol. 49:81–92. 2014. View Article : Google Scholar : PubMed/NCBI
16	Shiraishi T, Shinto E, Mochizuki S, Tsuda H, Kajiwara Y, Okamoto K, Einama T, Hase K and Ueno H: Mesothelin expression has prognostic value in stage II/III colorectal cancer. Virchows Arch. 474:297–307. 2019. View Article : Google Scholar : PubMed/NCBI
17	Kim H, Chung Y, Paik SS, Jang K and Shin SJ: Mesothelin expression and its prognostic role according to microsatellite instability status in colorectal adenocarcinoma. Medicine (Baltimore). 98:e162072019. View Article : Google Scholar : PubMed/NCBI
18	Lv J and Li P: Mesothelin as a biomarker for targeted therapy. Biomark Res. 7:182019. View Article : Google Scholar : PubMed/NCBI
19	Kanda Y: Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 48:452–458. 2013. View Article : Google Scholar : PubMed/NCBI
20	Inaguma S, Lasota J, Felisiak-Golabek A, Kowalik A, Wang Z, Zieba S, Kalisz J, Ikeda H and Miettinen M: Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression. J Pathol Clin Res. 3:268–278. 2017. View Article : Google Scholar : PubMed/NCBI
21	Inaguma S, Ito H, Riku M, Ikeda H and Kasai K: Addiction of pancreatic cancer cells to zinc-finger transcription factor ZIC2. Oncotarget. 6:28257–28268. 2015. View Article : Google Scholar : PubMed/NCBI
22	Inaguma S, Kasai K and Ikeda H: GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin. Oncogene. 30:714–723. 2011. View Article : Google Scholar : PubMed/NCBI
23	Inaguma S, Riku M, Hashimoto M, Murakami H, Saga S, Ikeda H and Kasai K: GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1. Cancer Res. 73:7313–7323. 2013. View Article : Google Scholar : PubMed/NCBI
24	Onda M, Willingham M, Nagata S, Bera TK, Beers R, Ho M, Hassan R, Kreitman RJ and Pastan I: New monoclonal antibodies to mesothelin useful for immunohistochemistry, fluorescence-activated cell sorting, Western blotting, and ELISA. Clin Cancer Res. 11:5840–5846. 2005. View Article : Google Scholar : PubMed/NCBI
25	Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C, Heiman D, Tarpey P, Danilova L, Drill E, Gibb EA, et al: Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 8:1548–1565. 2018. View Article : Google Scholar : PubMed/NCBI
26	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 : PubMed/NCBI
27	Chang MC, Chen CA, Hsieh CY, Lee CN, Su YN, Hu YH and Cheng WF: Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 424:449–458. 2009. View Article : Google Scholar : PubMed/NCBI
28	Servais EL, Colovos C, Rodriguez L, Bograd AJ, Nitadori J, Sima C, Rusch VW, Sadelain M and Adusumilli PS: Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clin Cancer Res. 18:2478–2489. 2012. View Article : Google Scholar : PubMed/NCBI
29	Masugi Y, Nishihara R, Hamada T, Song M, da Silva A, Kosumi K, Gu M, Shi Y, Li W, Liu L, et al: Tumor PDCD1LG2 (PD-L2) Expression and the lymphocytic reaction to colorectal cancer. Cancer Immunol Res. 5:1046–1055. 2017. View Article : Google Scholar : PubMed/NCBI