The role of mesothelin in tumor progression and targeted therapy

Abstract

Mesothelin, a glycosylphosphatidylinositol (GPI) anchored cell surface protein, is a potential target for antibody-based cancer therapy due to its high expression in mesothelioma, ovarian cancer, pancreatic cancer, cholangiocarcinoma and other cancers. The SS1P immunotoxin and MORAb-009 (amatuximab), a chimeric monoclonal antibody, are currently being evaluated in clinical trials. In this review, we discuss the role of mesothelin in cancer progression and provide new insights into mesothelin-targeted cancer therapy. Recent studies highlight three mechanisms by which mesothelin plays a role in cancer progression. First, mesothelin may aid in the peritoneal implantation and metastasis of tumors through its interaction with mucin MUC16 (also known as CA125). Second, mesothelin may promote cancer cell survival and proliferation via the NF-κB signaling pathway. Finally, mesothelin expression promotes resistance to certain chemotherapy drugs such as TNF-α, paclitaxel, and a combination of platinum and cyclophosphamide. However, its cancerspecific expression makes mesothelin a potential target for monoclonal antibody therapy. New human monoclonal antibodies targeting mesothelin have been isolated by phage display technology and may provide opportunities for novel cancer therapy.

Figure 1

Structure of mesothelin. The mesothelin precursor protein (71 kDa) is cleaved by furin to release its 31 kDa N-terminal megakaryocyte potentiating factor (MPF) and is displayed as mature mesothelin on the cell surface. Region I (residues 296–390) of mature mesothelin contains the binding site for SS1P/MORAb-009 and MUC16/CA125.

Figure 2

Role of mesothelin in cancer progression Overexpression of mesothelin leads to higher IL-6 production by constitutively activating NF-κB. High IL-6 can trigger the transcription protein 3 (Stat3), resulting in higher expression levels of the cyclin E/cyclin-dependent kinase (CDK2) complex, as well as speeding the G1-S transition. In addition, activation of NF-κB and Stat3 may induce expression of Bcl-xl and Bcl-2 and inhibit apoptosis signaling. Mesothelin can protect cancer cells from drug-induced apoptosis by stimulating Akt phosphorylation under PI3K activation or the MAPK/ERK signaling pathway to promote the expression of anti-apoptotic genes such as Bcl-2 and Mcl-1 or inhibit the expression of pro-apoptotic factors such as Bad and Bax.