Blocking the synthesis of estradiol, an estrogen hormone, in mice with malignant pleural mesothelioma (MPM) reduced tumor growth, researchers report, suggesting that therapeutic approaches to lower estradiol levels may be of help to people. The findings were published in Oncotarget, in the study “Reduction of estradiol in human malignant pleural mesothelioma tissues may prevent tumor growth, as implied by in-vivo and in-vitro models.”
The enzyme aromatase, involved in estrogen synthesis, is known to be biologically active in MPM cells and associated with poor survival in MPM patients. Although the role of estrogens in cancers is still controversial, they have been shown to promote growth in lung cancers, and some studies suggest estrogen may be involved in MPM progression. In fact, stopping estrogen production via exemestane, an aromatase inhibitor, has been shown to effectively block the growth of MPM cell lines in culture, and to treat mice with MPM.
Researchers hypothesized that exemestane works by reducing the levels of estradiol. Estrogen hormones can act in the cell via genomic pathways, which involve the regulation of particular genes through the binding of estrogen-estrogen receptor complexes to the DNA, and non-genomic pathways that involve G-protein coupled receptors, such as GPR30, and regulate cell proliferation, survival, or death by activating particular signaling cascades. The investigators, at the Regina Elena National Cancer Center in Rome, examined the contribution of each pathway by measuring the levels of each receptor.
Tumor samples from 57 patients with a median follow-up of five years after diagnosis first were analyzed and compared with samples from five healthy controls. Researchers found estradiol in 95 percent of the tumor samples, and found that estradiol levels negatively correlated with survival time in patients.
Next, the researchers used exemestane, which reduces estradiol, in normal mesothelium cells and five malignant mesothelium cell lines and found that the lowered levels led to reduced MPM cell growth. Mice were then injected with MPM cells, and their estradiol levels and tumor size significantly increased over the course of 50 days. But when the mice were treated with exemestane and re-examined at 50 days, their estradiol levels were significantly lower than at baseline, and no new tumors had developed.
After examining the expression of the receptors involved in estradiol activity, the researchers found GPR30 to be involved in tumor growth through interaction with estradiol. In fact, inhibiting GPR30 induced cell death and tumor shrinkage in a way similar to exemestane treatment.
“These findings are encouraging and possibly support further investigation of exemestane in the clinical MPM context as well as highlighting the opportunity to test new compounds,” the researchers concluded.
MPM, the most common type of mesothelioma, is resistant to conventional treatments, including radiation, chemotherapy, and surgery, and new insights into the molecular mechanisms that underlie MPM development are of particular importance.