Mesothelioma May Be Stopped by Blocking Plasma Membrane Receptor P2X7R

Another potential target for treating mesothelioma has been identified. It’s the plasma membrane receptor P2X7R.

A team of researchers from the University of Ferrara in Italy are reporting that it may be possible to stop mesothelioma by blocking P2X7R.

In the online edition of the journal Oncotarget, the researchers said they found P2X7R receptors present in malignant pleural mesothelioma cells.

However, those same receptors were entirely missing in the healthy mesothelial cells of people who are mesothelioma-negative. That distinction alone makes P2X7R a potential therapeutic target.

The researchers said their observations are valuable in part because P2X7R expression and its functioning in mesothelioma have not been previously reported. In other types of cancer, yes. In mesothelioma, no.

For this study, the researchers evaluated mesothelioma cells in lab dishes and mice, not in people. Even so, they heralded theirs as the first study to demonstrate the potentially useful effect of blocking P2X7R.

“[B]lockade effectively inhibits in vivo malignant pleural mesothelioma tumor growth,” they wrote. “Our findings might open the avenue for an exploratory trial to test the efficacy of P2X7R blockers in the therapy of malignant pleural mesothelioma.”

P2X7R Helps Mesothelioma Spread

In their research, the investigators drew upon earlier studies performed with other cancers to explore the functioning of P2 receptors.

P2 receptors — including P2X7R — are known as plasma membrane receptors for extracellular nucleotides. They promote cancer-triggering inflammation and support cancer spread.

P2X7R also gives an edge to cancer cells. This edge helps them flourish even in unfavorable conditions, such as those where sugar is in short supply. It also helps them with regard to a process known as extracellular matrix invasion.

P2X7R contributes a spark that fires up production of the signaling protein VEGF (vascular endothelial growth factor). VEGF promotes the formation of blood vessels that bring nourishment to tumors.

Mesothelioma Tumor Growth Reduced

The researchers cited past studies that linked P2X7R-mediated growth stimulation in human neuroblastoma cells to the PI3K/GSK3β/HIF-1α pathway. It was this linkage that led to testing of P2X7R blockers in human and mouse neuroblastoma.

A strong growth-inhibitory effect was seen resulting from that blockading. And there were other intriguing findings.

“Interestingly, we also observed that systemic administration of P2X7R blockers was more affective in tumor-bearing immunocompetent versus nude/nude mice, suggesting that the anti-tumor effect required an active immune response,” the researchers wrote.

In this new study, the researchers determined that human mesothelial cells cause P2X7R up-regulation.

“Cellular responses activated by the P2X7R agonist benzoyl ATP were barely detectable in all mesothelial cells types investigated,” they disclosed. “Nevertheless, we were able to clearly inhibit growth by treatment with P2X7R agonists or antagonists,” they said.

As for mesothelioma cells, the researchers relied on three lines for testing. They were MPP89, MSTO-211H and IST-MES2.

Efforts to blockade P2X7R delivered tantalizing results in each of the three mesothelioma cell lines. According to the researchers, tumor growth was reduced.

That is another reason why the researchers are excited about the potential of P2X7R inhibition. Of course, much more research is needed to determine whether the therapeutic target will fulfill its potential.

The title of the article is “P2X7 Targeting Inhibits Growth of Human Mesothelioma.”