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

Cited by 44 publications

(34 citation statements)

References 37 publications

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“…S5). These rat tumor results are in sharp contrast to the findings of others37 who reported strong luminal membrane Msln immunostaining in human extrahepatic bile duct cancers to more significantly correlate with liver and peritoneal metastases and with a more unfavorable patient survival outcome, while patients whose tumors expressed cytoplasmic Msln without luminal membrane staining had a more favorable prognosis. Even more compelling is our finding that the 50‐kDa form of Msln was expressed at significantly higher levels compared to the 40‐kDa form in the less aggressive BDEsp and TDE CC cholangiocarcinomas in situ and polarized TDE CC structures formed in 3‐D culture that express apical/luminal Msln cell‐surface immunoreactivity; the highly tumorigenic and more malignantly aggressive orthotopic BDEneu liver tumors and associated peritoneal metastases and the corresponding BDEneu and BDEneu‐Met cell lines, characterized by cytoplasmic Msln immunostaining, loss of cell polarity, and increased anaplasia, significantly overexpressed 40‐kDa Msln compared to the 50‐kDa form.…”

Section: Discussioncontrasting

confidence: 99%

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Manzanares

Campbell

Maldonado

et al. 2017

Hepatology Communications

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Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three‐dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40‐kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three‐dimensional culture. Moreover, coculturing of cancer‐associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40‐kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155–172)

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Section: Discussioncontrasting

confidence: 99%

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Manzanares

Campbell

Maldonado

et al. 2017

Hepatology Communications

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“…Mesothelin, a cell-surface protein expressed in nonmalignant mesothelial cells, is often aberrantly expressed in cholangiocarcinomas, and is associated with advanced-stage and metastatic disease, and unfavourable overall survival 144,145 . Thus, this protein is an attractive target for therapy.…”

Section: Emerging Molecularly-directed Therapiesmentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

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“…The association between mesothelin expression in tumor cells and unfavorable clinical outcome has been reported in several gastrointestinal malignancy including biliary adenocarcinoma [10], and gastric carcinoma [11]. However, there has also been conflicting results that demonstrated that mesothelin expression was associated with prolonged survival in patients with advanced stage in epithelial ovarian carcinomas [12].…”

Section: Introductionmentioning

confidence: 99%

Mesothelin expression is associated with poor outcomes in breast cancer

Xian

Ziober

et al. 2014

Breast Cancer Res Treat

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Background Mesothelin, previously shown to be expressed in triple negative breast cancer (TNBC), is a potential therapeutic target and prognostic marker in breast cancer. Methods We analyzed clinical data from two cohorts comprising of 141 patients treated between 2009 and 2011 at our institution (discovery cohort) and 844 patients from The Cancer Genome Atlas (TCGA) (validation cohort). Mesothelin expression was quantified by immunohistochemistry (IHC) or by RNA transcript levels as measured by whole-transcriptome sequencing in the discovery and validation cohorts respectively. Results In the discovery cohort, the median follow up was 3.55 years. Univariate analyses demonstrated that tumor size (hazard ratio (HR) =1.30, 95% confidence interval (CI) 1.11–1.51), positive (+) axillary lymph nodes (HR=3.34; 95% CI 1.51–7.39), and mesothelin expression (HR = 2.03; 95% CI 1.10–3.74) were associated with overall and disease-specific survival. We used a Cox-proportional hazard (Cox-PH) model to adjust for the two independent predictors of survival, namely (+) axilla lymph nodes and tumor size, and we found a significant association between mesothelin expression and overall and disease-specific survival in the discovery cohort (HR = 3.06, 95% CI 1.40–6.68). Using the TCGA dataset, we confirmed that, over a median follow-up of 16.0 months, patients with mesothelin-expressing tumors had poorer overall survival (HR=1.46; 95% CI 1.05–2.03). On Cox-PH multivariate analysis, mesothelin-positivity was an independent predictor of worse survival, after adjusting for (+) axillary lymph nodes and tumor size (HR = 1.69; 95%CI 1.17–2.42). Conclusions Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in TNBC tumors, especially in African American women. As there is no existing targeted therapy for TNBC, mesothelin may be a promising drug target for TNBC. Future work is needed to evaluate the efficacy of mesothelin directed targeted therapy in the treatment of breast cancer.

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

Cited by 44 publications

References 37 publications

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Mesothelin expression is associated with poor outcomes in breast cancer

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