Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

Abstract

The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, as well as ecto-nucleotidases regulate normal pancreatic cells and various cells within the pancreatic tumor microenvironment. In particular, we focus on the P2X7 receptor, P2Y2 and P2Y12 receptors, as well as A2 receptors and ecto-nucleotidases CD39 and CD73. Recent studies indicate that targeting one or more of these candidates could present new therapeutic approaches to treat pancreatic cancer. In pancreatic cancer, as much as possible of normal pancreatic function should be preserved, and therefore physiology of purinergic signaling in pancreas needs to be considered.

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

“…PDAC presents itself as a solid tumor with a complex tumor microenvironment (TME) that contributes to immunosuppression and poor efficiency of chemo-and radiotherapy [3]. The TME is made up of cellular and noncellular components, including cancer-associated fibroblasts, cancer infiltrating immune cells, extracellular matrix, various cytokines, and nucleotides, which all can interact with cancer cells and support tumor growth, immunosuppression, and metastasis [4,5].…”

Emerging roles of the solute carrier family in pancreatic cancer

“…87,90,91 Novak et al summarized the purinergic signaling in pancreatic cancer and indicated that PDAC cell lines release ATP through VNUT in response to several stimuli. 92 Furthermore, VNUT regulates the viability of pancreatic cancer cells by functioning as lysosomal ATP transporters, and extracellular nucleosides also promote anticancer immunity by inducing immunogenic cell death. 93,94…”

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

“…CD39 independent (non-canonical) adenosine production is enabled through NAD + conversion into AMP by CD38 (NAD + nucleosidase) and CD203a (ecto-nucleotide pyrophosphatase/phosphodiesterase 1), which is complemented by CD73 mediated AMP to adenosine conversion [166]. With respect to pancreatic cancer, adenosine signalling plays a key role in pancreatic exocrine physiology, and together with CD73 and CD39, has been extensively reported to be upregulated in PDAC and its TME, in preclinical work [167]. Interestingly however, in a murine model (BxPC-3-GFP cells in BALB/c mice) of pancreatic cancer, adenosine was shown to also have anti-tumourigenic effects by inducing cancer cell apoptosis.…”

“…Effector T-cells increased expression of A2aR in inflammation, is inhibitory to T-cell cytotoxicity and inhibits cytokine release. In NK cells, A2aR activation results in their suppression while in regulatory T-cells, expansion and increased immunosuppressant activity follows [167]. The role of A2aR in pancreatic cancer and its treatment is not yet well established.…”