Mesothelin is essential for tumor formation, progression and metastasis in lung cancer and mesothelioma, concludes a new study that provides insights into the underlying mechanisms of both diseases and may lead to new targeted therapies to fight them.
Mesothelin is normally expressed in mesothelial cells of the membranes lining the chest and abdominal cavities as well as the heart, and is undetectable in other body tissues. Previous studies have reported that mesothelin is abnormally expressed in almost all mesothelioma cases and in many solid tumors. In fact, up to 70 percent of patients with lung cancer — the leading cause of cancer death in the United States for both men and women — have high levels of mesothelin in their cancer cells.
Confirming these observations, researchers at West Virginia University (WVU) found mesothelin at higher levels in tissue samples from patients with non-small cell lung cancer (NSCLC) than in normal lung tissue. Also, lung carcinoma and mesothelioma experimental cell lines had increased levels of this protein, compared to non-cancerous cell lines.
To unravel mesothelin involvement in lung cancer and mesothelioma onset and progression, researchers genetically engineered lung and mesothelioma cell lines lacking the mesothelin gene. As a result, these cells were unable to grow and proliferate, nor could they form tumors.
By contrast, when the researchers induced mesothelin expression in a normal mesothelial cell line, they found that the cells acquired tumor-like features, such as increased proliferation and ability to form colonies. This suggested that mesothelin was essential for mesothelioma tumor cell transformation and progression.
During tumor progression, a cellular process called epithelial-to-mesenchymal transition (EMT) allows tumor cells to acquire cancer stem-cell (CSC) like properties, with increased ability to invade and migrate to distant organs. The team found that mesothelin regulated the expression of several CSC and EMT associated genes, controlling the fate of cancer cells and tumor progression.
Injection of mesothelin-deficient mesothelioma and lung cancer cells into experimental animal models further confirmed the role of this protein in tumor progression. In the absence of mesothelin, tumor burden dropped and the cancer cells were unable to migrate.
“We provide new evidence for the role of [mesothelin] in EMT regulation, tumorigenesis and metastasis,” wrote Xiaoqing He of WVU’s Department of Pharmaceutical Sciences. “Because of its importance in EMT and CSC regulation, [mesothelin] could be a potential therapeutic target for advanced and recurrent lung cancer and mesothelioma.”