The Role of Mesothelin Expression in Serous Ovarian Carcinoma: Impacts on Diagnosis, Prognosis, and Therapeutic Targets

Abstract

Mesothelin (MSLN) is a protein expressed in the mesothelial cell lining of the pleura, peritoneum, and pericardium; its biological functions in normal cells are still unknown. Experimental studies using knockout mice have suggested that this molecule does not play an important role in development and reproduction. In contrast, it has been observed that this molecule is produced in abnormal amounts in several malignant neoplasms, such as mesotheliomas and pancreatic adenocarcinomas. Many molecular studies have also demonstrated that mesothelin is overexpressed in HSOCs. Here, we discuss the current knowledge of mesothelin and focus on its role in clinical and pathological diagnoses, as well as its impact on the prognosis of HSOC. Moreover, regarding the binding of MSLN to the ovarian cancer antigen CA125, which has been demonstrated in many studies, we also report on signal transduction pathways that may play an important role in the spread and neoplastic progression of this lethal neoplasm. Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered an antigenic target for the treatment of many malignancies. Consequently, we also review the literature to report on mesothelin-targeting therapies for HSOC that have been recently investigated in many clinical studies.

Keywords: biomarker; mesothelin; mesothelin-targeting therapy; ovarian carcinoma.

Figure 1

Two individual examples of advanced serous ovarian carcinoma showing diffuse mesothelin immunoreactivity: (A) score 4+, ×100; (B) score 3+, ×100. A personal example of STIC with a small nest of invasive serous carcinoma in a woman with BRCA-1 mutation and a previous history of breast cancer, showing strong immunoreactivity for MSLN in both lesions (C). Arrows indicate STIC, arrowheads indicate invasive serous carcinoma ×40.

Figure 2

Schematic and simplified representation of the pathway involving the binding of CA125 with mesothelin for the migration of neoplastic cells and metastatic diffusion in advanced serous ovarian carcinoma.

Figure 3

Schematic and simplified representation of the main therapeutic strategies that use mesothelin as a target. (A) PE translocated in cytosol and killed cells, catalysing protein synthesis and initiating programmed cell death. DM4 binding to tubulin disrupts the microtubule polymerisation, causing cell cycle arrest, apoptosis, and the killing of the dividing cells. (B) Attached to MSLN, CAR T cells become activated and stimulate the host immune system with the production of inflammatory cytokines. In CR-207, Listeria monocytogenes (Lm) and its antigens into the cytosol can be loaded onto major histocompatibility complex (MHC) I and MCH II, causing the activation of potent CD4 helper lymphocytes and CD8 cytotoxic lymphocytes, or activating pro-inflammatory genes, which can amplify the cytotoxic effect caused by inflammatory cytokines.