Researchers at the Nagoya University Graduate School of Medicine in Japan have shown that increased levels of a cell surface protein called urokinase-type plasminogen activator receptor (uPAR) are associated with poor prognosis in malignant mesothelioma.
The study, “Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma,” published in the journal Oncotarget, shows that uPAR levels negatively correlate with sensitivity to the chemotherapy drug Platinol (cisplatin), suggesting that combining uPAR inhibitors with Platinol may be a promising therapeutic approach for mesothelioma.
The vast majority of mesothelioma cases are caused by exposure to asbestos, a set of six naturally occurring silicate minerals. The prognosis of malignant mesothelioma is poor, as this type of cancer is aggressive and highly resistant to chemotherapy. It is therefore critical to identify other molecules that may be key for the early diagnosis and development of therapies for this disease.
Although uPAR is usually expressed in various organs, including the colon, kidney, and bone marrow, its levels increase in certain conditions, such as the progression of various tumors.
“Indeed, uPAR is overexpressed in some human cancers, including breast, gastric, and lung cancer, and it has been associated with poor prognosis, particularly in cases of leukemia, lung, prostate and breast cancer,” the authors wrote. “Here, for the first time, we measured and modulated uPAR expression in asbestos-induced [malignant mesothelioma] tissues and cells to determine downstream signaling alterations and its impact on chemotherapy.”
In the study, researchers used rats with asbestos-induced mesothelioma, and found that uPAR levels were elevated in both the epithelioid and sarcomatoid subtypes of the disease. The higher the levels of this protein, the poorer the prognosis of the animals.
Similar observations were made in blood samples and tissues from mesothelioma patients, which also presented significantly high levels of this protein.
The researchers found that uPAR levels were associated with the proliferative, migratory, and invasive behavior of mesothelioma cells, and that inhibiting the expression of this protein significantly suppressed proliferation as well as the migratory and invasive properties of the cells.
Importantly, their results showed that expression of uPAR was associated with sensitivity to Platinol, a chemotherapy drug. While inhibition of uPAR expression rendered the cells less resistant to Platinol, the reverse occurred when they enhanced the expression of uPAR.
These results suggest that uPAR can serve as a biomarker for malignant mesothelioma prognosis. But the researchers also believe that inhibiting uPAR expression may be a strategic therapy to increase sensitivity to chemotherapy with Platinol, improving the prognosis of mesothelioma patients with high levels of this protein.