Accelerated Tumor Progression in Mice Lacking the ATP Receptor P2X7

Abstract

The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1b and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. Cancer Res; 75(4); 635-44. Ó2014 AACR.

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

“…This validates that the P2X7R allosteric inhibitor AZ10606120 has anti‐proliferative effects both in vitro and in vivo . This inhibitor is not yet widely tested in cancer, but two studies show that similar anti‐proliferative effect of the inhibitor was detected in subcutaneous cancer induced by HEK293‐hP2X7 or B16 melanoma cells 1, 20…”

“…One explanation is that these seemingly opposite effects depend on expression/interaction of presumed proapoptotic P2X7A isoform and trophic isoform P2X7B 21. Third, P2X7R is involved in inflammation and immune system modulation, which can potentially affect tumour growth and progression 1, 22…”

P2X7 receptor in skin biology and diseases

“…P2X7 on immune cells also plays an important role in preventing melanoma progression by promoting anti-tumour immune responses. B16 melanoma growth and metastasis is increased in P2X7 deficient mice or wild-type chimeric mice transplanted with P2X7-deficient bone marrow compared to control mice [102] . P2X7 may also play an important role in BCC and SCC.…”

“…Studies both in vitro and ex vivo have demonstrated a role for P2X7 in the process of wound healing. P2X7 is important for early cell migration and infiltration of immune cells required for wound healing, with P2X7 deficient cells showing a reduced migratory ability in an in vitro wound repair model suggesting that lack of P2X7 affects chemotaxis [102] . P2X7 also promotes the release of VEGF from primary monocytes, important for control of angiogenesis and wound healing [103] .…”

“…Allergic contact dermatitis P2X7 blockade or deficiency impairs CHS [89] Irritant contact dermatitis P2X7 blockade or deficiency impairs croton oil-induced oedema, IL-1b production and neutrophil infiltration [69] Psoriasis ND Cutaneous graft-vs-host disease P2X7 blockade or deficiency increases survival and reduces disease severity, serum concentrations of IFN-g, TNF-a and IL-6 in allogeneic mouse models [98,99] Wound healing P2X7 deficient macrophages display reduced migration in an in vitro wound repair model [102] Skin transplantation P2X7 blockade or deficiency prevents allogeneic skin transplant rejection [109] Melanoma ATP injection impairs A375 melanoma cell growth in immuno-compromised mice [120] P2X7 blockade inhibits B16 melanoma cell growth in immuno-competent mice [121,122] P2X7 deficiency impairs B16 melanoma cell migration in vitro [102] P2X7 deficiency in host leads to increased B16 melanoma growth and metastasis [102] Basal cell carcinoma ND Squamous cell carcinoma P2X7 deficiency in host enhances chemical-induced carcinogenesis [18] BzATP injection led to tumour apoptosis [18] ATP: Adenosine triphosphate; BzATP: 2',3'-O-(4-benzoyl) benzoyl ATP; CHS: Contact hypersensitivity; IFN: Interferon; IL: Interleukin; ND: Not determined; TNF: Tumour necrosis factor. Table 3 Roles of the P2X7 receptor in human skin diseases…”