Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Abstract

The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.

Purinergic Signalling: Therapeutic Developments

“…P2X7R are expressed in pancreatic cancer cells. P2X7R antagonists are likely to be effective therapeutic agents ( Giannuzzo et al, 2016 ).…”

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…[13][14][15] In addition, the P2X7 receptor promotes VEGF release to facilitate angiogenesis, cell invasion, and metastasis. 10,16,17 Numerous studies indicate that P2X7 is overexpressed in several cancers; [18][19][20] however, tumor-promoting pathways activated by P2X7 are not completely unraveled.…”

P2X7R as an independent prognostic indicator in gastric cancer

“…On the other hand, it is considered that inhibition of P2XR7 may be a good strategy for the treatment of various cancers, including GC. Although perhaps too early for human use, a P2X7R inhibitor has recently been tested on pancreatic cancer cells and reported to have anticancer activity [10]. In two different studies supporting this, Blockade of P2X7R decreased growth and metastases of implanted tumors, such as hepatocellular carcinoma and breast cancer [30,31].…”

“…The P2X receptors (P2XR) identified as seven subunits (P2X1-7) are ATP-gated calcium-permeable cationic channels. Of these, in particular, the P2X7R is of increasing attention as a possible therapeutic target for the treatment of some diseases, including certain cancers [8][9][10][11]. P2X7R plays an important role in regulating inflammatory events.…”