Abstract
Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas representing 90% of pancreatic malignancies [1]
The only curative therapy available is surgical resection followed by adjuvant therapy [14], but 80% of PDAC patients have an advanced or metastatic disease that is ineligible to surgery [15]
MUC16 and MSLN co-expression levels were found to be increased at the invasion front of PDAC-derived tissues in comparison to that of detected in the stroma—MUC16 high/MSLN high expression group was strongly associated with large tumors, invasion of other distant organs and lymphatic permeation [52]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas representing 90% of pancreatic malignancies [1]. Projections indicate that a more than two-fold augmentation of PDAC cases is expected in the ten years. One reason for this dramatic increase is its relationship with obesity and type-2 diabetes, two modern health drivers in PDAC etiology [6,7]. Efficacy and outcome of PDAC treatments are determined by the disease stage at the time of diagnosis, which is done at an advanced stage most of the time. Novel strategies for the identification of early-stage tumors and efficient targeted therapies have gained valuable interest in recent years. The role of MSLN as a pro-tumorigenic factor and a therapeutic target in PDAC has gained a renewed interest. We first discuss the different functions of MSLN during PDAC progression, to emphasize on the MSLN-targeted agents that are currently under clinical development for diagnosis and PDAC treatment
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