Mesothelin, a protein found on cell surfaces and in serum, has emerged as a promising target for immunotherapy-based treatment approaches for several malignancies with poor prognoses and limited treatment options, including mesothelioma, pancreatic cancer, and ovarian cancer. Investigating novel approaches to optimize delivery and identifying combinations of agents to synergistically improve therapeutic response will be the next steps in bringing mesothelin-targeted therapies into the clinical setting.
Mechanisms of Mesothelin Overexpression in Cancer
Mesothelin was first identified as the cell-surface antigen CAK1 in 19921 and characterized as a 40-kDa glycoprotein found on the surface of mesotheliomas and ovarian cancers.2 Although it is commonly a membrane-bound, glycosylphosphatidylinositol-linked protein, the extracellular domain of mesothelin is shed from tumor cells,3 and some data suggest that detection of serum mesothelin may be a useful marker in cancer diagnostic procedures.4
Although the biologic function of mesothelin has not been completely elucidated, it is thought to contribute to cell adhesion, differentiation, and signal transduction in cancer cells.5 Overexpression in cancer cells may promote proliferation, cell migration and spread, chemotherapy resistance, and inhibition of apoptosis through activation of multiple intracellular pathways, such as the NF-κB, MAPK, and PI3K pathways.6,7 Binding of mesothelin to cancer antigen (CA) 125, also known as mucin 16 (MUC16), in the neoplastic setting suggests its role in cell adhesion and potential as a target for anticancer therapy,8 particularly in ovarian cancer, in which mesothelin is implicated in promoting peritoneal metastases (Figure).9 Mesothelin also been shown to activate MAPK pathway signaling independent of MUC16 expression.10
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