Mesothelin

Mesothelin Overview

Mesothelin is a 40 kDa glycoprotein expressed on the surface of mesothelial cells, which line the pleura, peritoneum, and pericardium. It is derived from a 70 kDa precursor protein (prodynorphin) by proteolytic cleavage. While normally found at low levels on healthy mesothelial cells, its expression is significantly upregulated in several types of cancer, making it a valuable biomarker and a promising therapeutic target.

The soluble form of mesothelin, often referred to as soluble mesothelin-related peptide (SMRP), can be shed into the bloodstream and other body fluids. Measurement of SMRP in serum is primarily used as a tumor marker for malignant mesothelioma, and increasingly, for other mesothelin-expressing cancers.

Mesothelin Biology and Function

Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored protein. After its precursor is cleaved, the N-terminal fragment (megakaryocyte potentiating factor, MPF) is secreted, and the C-terminal fragment remains membrane-bound as mesothelin. While its precise physiological function is not fully understood, it is thought to play a role in cell adhesion, particularly in cancer cells.

In cancer, mesothelin has been implicated in several processes:

• Cell Adhesion: It interacts with CA-125 (MUC16), a mucin expressed on ovarian cancer cells, promoting heterotypic cell adhesion and potentially facilitating metastasis.
• Cell Proliferation and Survival: Evidence suggests mesothelin can promote tumor cell growth and survival through various signaling pathways.
• Immune Evasion: It may contribute to creating an immunosuppressive microenvironment within the tumor.

The shedding of mesothelin from the cell surface into the bloodstream allows for its use as a non-invasive diagnostic and monitoring biomarker.

Indications for Mesothelin Testing

Testing for soluble mesothelin-related peptide (SMRP) is primarily indicated for:

1. Diagnosis of Malignant Mesothelioma: SMRP is the most established biomarker for malignant pleural mesothelioma (MPM), a highly aggressive cancer strongly associated with asbestos exposure. Elevated levels can aid in distinguishing mesothelioma from benign pleural diseases.
2. Monitoring Malignant Mesothelioma Treatment: SMRP levels can be used to track disease progression or response to chemotherapy, surgery, or other treatments. Decreasing levels often indicate a positive response, while rising levels may suggest recurrence or disease progression.
3. Prognostic Indicator: High baseline SMRP levels are often associated with a poorer prognosis in mesothelioma patients.
4. Screening for Mesothelioma: In individuals with significant asbestos exposure, SMRP may be used as part of a screening panel, though its utility for early detection in asymptomatic individuals is still under investigation.
5. Other Cancers: Investigational use in other mesothelin-expressing cancers such as ovarian cancer, pancreatic cancer, and certain lung adenocarcinomas, where it may correlate with tumor burden or serve as a target for therapy.

Mesothelin in Malignant Mesothelioma

Malignant mesothelioma is a rare but aggressive cancer originating from the mesothelial cells that line the lungs (pleural mesothelioma), abdomen (peritoneal mesothelioma), or heart (pericardial mesothelioma). Exposure to asbestos is the primary risk factor.

• Diagnostic Aid: Serum SMRP levels are elevated in a significant proportion (approximately 70-80%) of patients with epithelial and biphasic types of mesothelioma, making it a valuable tool alongside imaging and biopsy. SMRP is particularly useful in differentiating mesothelioma from benign asbestos-related pleural effusions or other lung diseases.
• Monitoring Disease: Changes in SMRP levels often correlate with clinical course. A decrease post-treatment is generally indicative of a response, while an increase suggests progression or recurrence.
• Prognostic Value: Patients with higher SMRP levels at diagnosis tend to have more advanced disease and shorter survival.

It's important to note that SMRP is less sensitive in the sarcomatoid subtype of mesothelioma, which expresses lower levels of mesothelin.

Mesothelin in Other Cancers

Beyond mesothelioma, mesothelin is overexpressed in several other aggressive cancers, making it an area of active research for both diagnostic and therapeutic purposes:

• Ovarian Cancer: Mesothelin is highly expressed in many epithelial ovarian cancers. Elevated serum SMRP levels can be detected in a subset of patients and are being investigated as a complementary biomarker to CA-125, particularly in distinguishing benign from malignant pelvic masses. Its interaction with CA-125 on ovarian cancer cells is thought to play a role in peritoneal metastasis.
• Pancreatic Adenocarcinoma: A high percentage of pancreatic adenocarcinomas also show mesothelin overexpression. Serum SMRP is being explored as a potential biomarker for diagnosis, prognosis, and monitoring treatment response in this challenging cancer.
• Lung Adenocarcinoma: Mesothelin is expressed in some non-small cell lung cancers, particularly adenocarcinomas. While not a primary biomarker, its presence is relevant for targeted therapeutic approaches.
• Gastric Cancer: Overexpression has also been observed in certain gastric cancers, with ongoing research into its clinical utility.

The role of SMRP as a tumor marker in these cancers is still largely investigational, often used in research settings or as a complement to established markers.

Interpreting Mesothelin Levels

Reference ranges for soluble mesothelin-related peptide (SMRP) can vary between laboratories and assays, but typical cut-off values for malignancy are often around 1.0-2.0 nM (nanomoles per liter) or ng/mL, depending on the unit reported.

• Normal Healthy Individuals: Generally, SMRP levels are very low, often below 1.0 nM.
• Malignant Mesothelioma: Significantly elevated levels (often > 2 nM, and sometimes much higher) are strongly indicative of mesothelioma. The degree of elevation often correlates with tumor burden.
• Other Cancers: Moderately elevated levels may be observed in ovarian, pancreatic, and certain lung cancers, though typically not as high as in advanced mesothelioma.
• Benign Conditions: Slight elevations may sometimes be seen in benign inflammatory conditions affecting the mesothelium, such as benign asbestos pleural effusions, chronic kidney disease, or other inflammatory conditions, but these are usually not as high as in malignancy.

It is crucial to interpret SMRP results in conjunction with clinical history (especially asbestos exposure), physical examination, imaging studies (CT, MRI, PET scans), and biopsy results. A single elevated SMRP level is not sufficient for a diagnosis of cancer.

Mesothelin as a Therapeutic Target

The high and relatively specific overexpression of mesothelin on the surface of several aggressive cancers, while being minimally expressed on normal tissues, makes it an attractive target for cancer therapy. Several mesothelin-targeted therapies are under investigation:

• Antibody-Drug Conjugates (ADCs): These drugs consist of an antibody that binds to mesothelin, linked to a potent cytotoxic agent. Once the ADC binds to mesothelin-expressing cancer cells, it is internalized, releasing the chemotherapy drug inside the cell, thus minimizing systemic toxicity. Examples include anetumab ravtansine and SS1P (immunotoxin).
• Chimeric Antigen Receptor (CAR) T-cell Therapy: This involves genetically engineering a patient's own T-cells to express a CAR that specifically recognizes and binds to mesothelin on cancer cells, leading to their destruction. This is an active area of research for mesothelioma and other mesothelin-positive solid tumors.
• Monoclonal Antibodies: Antibodies that bind to mesothelin, such as amatuximab, are being developed to block mesothelin's activity or to mediate immune cell killing.
• Bispecific Antibodies: These antibodies are designed to bind to both mesothelin on cancer cells and an immune cell (e.g., a T-cell), bringing the immune cell into close proximity to the tumor cell to facilitate its destruction.

These targeted therapies hold significant promise, particularly for mesothelioma and pancreatic cancer, which have limited treatment options.

Frequently Asked Questions (FAQ)

References

1. National Cancer Institute (NCI). (n.d.). Mesothelin. NCI Dictionary of Cancer Terms. Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mesothelin
2. American Cancer Society (ACS). (2023). Malignant Mesothelioma. Retrieved from https://www.cancer.org/cancer/types/mesothelioma/about/what-is-mesothelioma.html
3. Pass, H. I., & Vogelzang, N. J. (Eds.). (2018). *Malignant Pleural Mesothelioma*. Springer.
4. Hassan, R., & Ho, M. (2008). Mesothelin-targeted immunotherapies for cancer. *Cancer Immunity*, 8(3), 3.
5. Creaney, J., & Robinson, B. W. (2017). Mesothelin-based biomarkers in malignant mesothelioma. *Translational Lung Cancer Research*, 6(3), 299-306.
6. Bhattacharya, R., & Ho, M. (2015). Mesothelin: biological functions and therapeutic applications. *Current Drug Targets*, 16(11), 1073-1090.