P2X7 targeting inhibits growth of human mesothelioma

Our plain-English summary of P2X7 targeting inhibits growth of human mesothelioma, by F. Amoroso, E. Salaro, S. Falzoni, et al (Oncotarget, 2016).

The study

• Authors: F. Amoroso, E. Salaro, S. Falzoni, P. Chiozzi, A.L. Giuliani, G. Cavallesco, P. Maniscalco, A. Puozzo, I. Bononi, F. Martini, M. Tognon, F. Di Virgilio
• Journal: Oncotarget
• Published: 2016;7(31):49664-49676
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor refractory to anti-blastic therapy. MPM cells show several genetic and biochemical defects, e.g. overexpression of oncogenes, downregulation of onco-suppressor genes, dysregulation of microRNA, or alteration of intracellular Ca2+ homeostasis and of apoptosis. No information is as yet available on purinergic signalling in this tumor. Signalling via the P2X7 (P2RX7 or P2X7R) purinergic receptor is attracting increasing attention as a pathway involved in cancer cell death or proliferation. In this report we show that the P2X7R is expressed by three MPM cell lines established from MPM patients but not by mesothelial cells from healthy subjects (healthy mesothelial cells, HMCs). MPM cell proliferation was inhibited by in vitro incubation in the presence of selective P2X7R antagonists, as well as by stimulation with the P2X7R agonist BzATP. Systemic administration of the selective P2X7R blocker AZ10606120 inhibited in vivo growth of MPM tumors whether implanted subcutaneously (s.c.) or intraperitoneally (i.p.). Our findings suggest that the P2X7R might be a novel target for the therapy of mesothelioma.

In plain English

This laboratory study used human malignant pleural mesothelioma cells grown in dishes and in mice. It did not study asbestos exposure. The authors measured a receptor, P2X7R, in healthy mesothelial cells from non-cancer patients, three mesothelioma cell lines (MPP89, IST-MES2, MSTO-211H) and SV40-immortalized mesothelial cells. The receptor's genetic message was virtually absent in healthy cells. Among mesothelioma lines it was highest in MPP89 and barely detectable in IST-MES2, and receptor protein was low. In dishes, the drugs caused no significant drop in healthy cell numbers and no LDH release, a marker of cell damage. In mesothelioma cells, receptor blockers fully stopped MSTO-211H growth, while the stimulating drug BzATP promoted it. In MPP89 cells, BzATP stopped growth, but the blocker AZ10606120 had a negligible effect. In mice, AZ10606120 cut MSTO-211H tumor size by 50% at removal. Final IST-MES2 tumor size did not differ significantly from placebo. In mice with abdominal tumors, treated animals showed less tumor spread and no signs of discomfort. The authors concluded this might open the way to an exploratory trial of these blockers in malignant pleural mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiment using human cell lines in vitro and human tumor cells transplanted into immunocompromised (nude/nude) mice
• Who was studied: Healthy human mesothelial cells from biopsies of young non-cancer pneumothorax patients (age 29–35), three malignant pleural mesothelioma cell lines (MPP89, IST-MES2, MSTO-211H), and SV40-immortalized mesothelial cells. Mouse experiments used 5 (MSTO-211H) or 3 (IST-MES2) mice per treatment group, and 3 mice per group for the intraperitoneal MPP89 experiment.
• Exposure: No asbestos exposure was studied. Cells were treated with the receptor blockers AZ10606120 and oxidized ATP (oxoATP), or with the stimulating drug BzATP. Mice received AZ10606120 or placebo every two days. For tumors under the skin, the drug was injected into the tumor mass. For MPP89 tumors, it was injected into the abdomen.
• Main results:
  • In healthy mesothelial cells, the P2X7R genetic message was virtually absent.
  • MPP89 mesothelioma cells had a P2X7R genetic message level three fold higher than the other cell lines, including the THP-1 reference cells.
  • IST-MES2 cells had a barely detectable P2X7R genetic message.
  • The authors concluded from the protein measurements that mesothelioma cells express P2X7R at a low level.
  • BzATP raised the calcium level inside all cell lines except the healthy mesothelial cells.
  • In dishes, healthy mesothelial cells showed no significant decrease in cell number and no LDH release with the receptor-targeting drugs.
  • In dishes, MSTO-211H cell growth was fully blocked by oxoATP or AZ10606120, but BzATP promoted their growth.
  • In dishes, MPP89 cell growth was fully inhibited by BzATP or oxoATP, while AZ10606120 had a negligible effect.
  • In mice with MSTO-211H tumors under the skin, AZ10606120 led to a 50% reduction in tumor size at the time of removal.
  • In mice with IST-MES2 tumors, the placebo-treated tumors also shrank. At day 15, the size of the removed tumors did not differ significantly between the placebo and AZ10606120 groups.
  • In mice with MPP89 tumors in the abdomen, the AZ10606120-treated mice showed no detectable signs of discomfort, while the placebo-treated mice did.
  • Placebo-treated mice with abdominal tumors had enlarged livers and spleens. AZ10606120-treated mice did not.
• The authors' conclusion: The authors concluded that their findings might open the way to an exploratory trial testing P2X7R blockers in the therapy of malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that the cell culture data do not allow them to conclude that P2X7R is the factor supporting the growth of the cells without serum.
  • The authors stated that tumors placed under the skin of the hip do not faithfully reproduce the natural environment in which mesothelioma grows.
  • In placebo-treated mice at later time points, connective tissue in the abdomen distorted the light signal. This prevented accurate measurement of tumor spread.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Apoptosis, Mesothelial Cells.

Related studies

• Sialic acid-binding lectin from bullfrog eggs inhibits human malignant mesothelioma cell growth in vitro and in vivo — T. Tatsuta, T. Satoh, et al. (2018)
• Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth — D.A. Altomare, H. You, et al. (2005)
• Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma — T. Villanova, I. Gesmundo, et al. (2019)
• The endoplasmic reticulum mitochondrial calcium cross talk is downregulated in malignant pleural mesothelioma cells and plays a critical role in apoptosis inhibition — S. Patergnani, C. Giorgi, et al. (2015)
• HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status — W.B. Ou, J. Zhu, et al. (2015)
• Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy — M.A. Hoda, A. Mohamed, et al. (2011)

Browse more research in Oncotarget, or return to medical research.