Mesothelin

• Mesothelin is a cell-surface glycoprotein involved in cell adhesion and signaling.
• It is overexpressed in many aggressive cancers, including mesothelioma, pancreatic, and ovarian cancers.
• Mesothelin contributes to cancer progression by promoting cell proliferation, invasion, and metastasis.
• It serves as a promising biomarker for early detection, prognosis, and monitoring of certain malignancies.
• Targeting Mesothelin is an active area of research for developing novel cancer therapies.

What is Mesothelin and Its Biological Function?

Mesothelin is a 40 kDa glycosylphosphatidylinositol (GPI)-anchored cell-surface glycoprotein that is derived from a 70 kDa precursor protein. In healthy individuals, Mesothelin is expressed at low levels on the mesothelial cells lining the pleura, peritoneum, and pericardium, as well as on some epithelial cells. Its precise normal biological function is not fully understood, but research suggests it may be involved in cell-to-cell adhesion and cellular signaling pathways.

Studies indicate that Mesothelin can interact with MUC16 (CA125), another cell-surface glycoprotein, which is thought to play a role in cell adhesion and migration. This interaction is believed to be important in both normal physiological processes and pathological conditions, particularly in cancer development where it can facilitate tumor cell dissemination. The low expression in normal tissues makes its overexpression in cancer a significant area of study.

Mesothelin’s Role in Cancer Development

Mesothelin’s role in cancer development is extensive, as it is significantly overexpressed in several aggressive malignancies, making it a key player in tumor biology. Its overexpression is particularly notable in mesothelioma, pancreatic adenocarcinoma, ovarian cancer, and certain types of lung and gastric cancers. This elevated expression contributes to various aspects of tumor progression, including enhanced cell proliferation, resistance to apoptosis, increased invasiveness, and metastatic potential.

In cancerous cells, Mesothelin can promote tumor growth by activating signaling pathways that drive cell division and survival. It also facilitates the adhesion of cancer cells to mesothelial surfaces, which is a critical step in the metastasis of peritoneal and pleural cancers. For instance, in malignant pleural mesothelioma, Mesothelin is overexpressed in nearly all cases, contributing to the aggressive nature of the disease. According to the World Health Organization (WHO), mesothelioma remains a challenging cancer with a poor prognosis, highlighting the need for effective therapeutic targets like Mesothelin.

The mechanisms by which Mesothelin contributes to cancer include:

• Promoting cell proliferation and survival.
• Enhancing cell migration and invasion.
• Facilitating tumor cell adhesion to mesothelial surfaces.
• Inducing epithelial-mesenchymal transition (EMT), a process linked to metastasis.

Mesothelin as a Biomarker and Its Clinical Significance

The consistent overexpression of Mesothelin in various cancers has established its importance as a biomarker with significant clinical utility. As a biomarker for disease, Mesothelin can be detected in both tumor tissue and in the serum of patients, making it valuable for several clinical applications. Serum Mesothelin-related protein (SMRP) levels, a soluble form of Mesothelin, are often elevated in patients with mesothelioma, pancreatic cancer, and ovarian cancer, serving as a non-invasive tool for diagnosis, prognosis, and monitoring treatment response.

In clinical practice, elevated SMRP levels can aid in the early detection of mesothelioma, especially in individuals with a history of asbestos exposure, where early diagnosis is critical for improving outcomes. Furthermore, changes in SMRP levels during treatment can indicate whether a therapy is effective or if the disease is progressing or recurring. Mesothelin research and clinical significance extend beyond its role as a diagnostic and prognostic marker; it is also a highly attractive target for novel cancer therapies. Immunotherapies, such as antibody-drug conjugates and chimeric antigen receptor (CAR) T-cell therapies, are being developed to specifically target Mesothelin-expressing cancer cells, offering new hope for patients with these difficult-to-treat malignancies.