1. Biotech

Mesothelin: A New Target for Cancer Therapy

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Structure and function of mesothelin

The MSLN gene is located in chromosome 16p13. It contains 17 exons, with a cDNA length of about 2138bp, has a 1884-bp open reading frame, and encodes the precursor protein of 628 amino acids (69 kDa). This precursor protein can be hydrolyzed by furin protease into two parts: mesothelin in the size of 40 kDa fragments and 31 kDa secreted fragments called megakaryocyte colony-stimulating factor (MPF).

Like many GPI-anchored proteins, mesothelin is shed to produce soluble mesothelin-related peptides (SMRP), which are commonly used as markers to detect malignant mesothelioma. Due to the presence of multiple proteases in the extracellular environment, mesothelin can be cleaved at different extracellular sites. On cells expressing mesothelin, seven major cleaved sites are near the membrane end, resulting in the production of membrane-bound truncated mesothelin.

GPI-linked proteins are usually involved in cell signaling and adhesion, so mesothelin may play a role in these biological processes, which, in normal physiological conditions, is still unclear. MSLN knockout mice have normal developmental and reproductive abilities, suggesting that mesothelin function is not essential for life. However, in MSLN knockout mice, the ultrastructure of the mesothelin membrane is affected, indicating that mesothelin may affect the formation of the tumor microenvironment. The growth of cancer cells in the abdominal cavity of MSLN knockout mice is significantly reduced compared with wild-type mice. Mesothelin or MPF supplementation stimulates lung cancer growth in MSLN knockout mice, which verifies the role of mesothelin in tumor cell adhesion, migration, and metastasis.

Role of mesothelin in cancer and signaling

Mesothelin is expressed in many solid tumors, most commonly in mesothelioma, epithelial ovarian, and pancreatic cancers, as well as in lung and uterine malignancies and bile duct cancer. Mesothelioma and ovarian cancer have the highest expression of mesothelin, and higher expression is associated with advanced tumor stage and higher metastasis rate. In stage IV colorectal cancer, high mesothelin expression is directly associated with chemotherapy resistance, aggressiveness, and poor prognosis. In contrast, the data from pancreatic cancer seem to indicate that despite the expression of mesothelin, it is not associated with cancer aggressiveness. This suggests that the expression of mesothelin and its relationship with prognosis and aggressiveness are tumor-specific.

The interacting protein of mesothelin is CA125/MUC16, a member of the mucin family, which is expressed in ovarian cancer and malignant mesothelioma. The interaction between CA125/MUC16 and mesothelin mediates heteromorphic cell adhesion in vitro and is therefore considered a potential mechanism for peritoneal metastasis of ovarian tumors. The binding of CA125/MUC16 to mesothelin down-regulates DKK1 (Dickkopf-1, a WNT signaling inhibitor) through the SGK3/FOXO3 signaling pathway, thus promoting migration. Blocking the binding restores DKK1 levels and prevents metastasis of ovarian cancer.

Soluble mesothelin binds to surface-anchored mesothelin, triggering matrix metalloproteinase-7 (MMP-7) expression via the ERK1/2 (extracellular signal-regulated kinase), Akt, and JNK (c-Jun N-terminal kinase) signaling pathways, leading to enhanced migration and aggressiveness. The overexpression of mesothelin in ovarian cancer cells has a similar effect and is significantly correlated with the expression of MMP-7. In addition, mesothelin binding to CA125/MUC16 also triggers the expression of MMP-7 through the p38 MAPK pathway in pancreatic ductal adenocarcinoma.

In addition, pancreatic cancer cell lines overexpressing mesothelin significantly increase their proliferation and accelerate the cell cycle process compared with mesothelin-silencing cell lines. Overexpression of mesothelin leads to constitutive activation of STAT3, resulting in increased expression of cyclin E and cyclin E/cyclin-dependent kinase 2 (CDK2) complexes, and faster G1-S conversion.

Mesothelin targeted therapies

As medical research moves from traditional frameworks towards more personalized approaches to cancer treatment, there is a necessity to understand tumor-specific antigens. Since mesothelin expression is limited in normal tissues and is overexpressed in several malignancies, it is an ideal candidate for targeted therapy. Results have been shown to be safe from several clinical trials of immunotherapy drugs targeting mesothelin, including immunotoxin therapy, monoclonal antibodies, vaccines, antibody-conjugated drugs, CAR T cells, CAR-NK cells, and α-targeted therapies. These novel therapies offer hope for the treatment of MSLN-positive tumors.

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