Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

Abstract

Adenosine 5'-triphosphate (ATP), other nucleotides, and the nucleoside analogue, adenosine, all have the capacity to modulate cellular signaling pathways. The cellular processes linked to extracellular purinergic signaling are crucial in the initiation, evolution, and resolution of inflammation. Injured or dying cells in the pancreatobiliary tract secrete or release ATP, which results in sustained purinergic signaling mediated through ATP type-2 purinergic receptors (P2R). This process can result in chronic inflammation, fibrosis, and tumor development. In contrast, signaling via the extracellular nucleoside derivative adenosine via type-1 purinergic receptors (P1R) is largely anti-inflammatory, promoting healing. Failure to resolve inflammation, as in the context of primary sclerosing cholangitis or chronic pancreatitis, is a risk factor for parenchymal and end-organ scarring with the associated risk of pancreatobiliary malignancies. Emerging immunotherapeutic strategies suggest that targeting purinergic and adenosinergic signaling can impact the growth and invasive properties of cancer cells, potentiate anti-tumor immunity, and also block angiogenesis. In this review, we dissect out implications of disordered purinergic responses in scar formation, end-organ injury, and in tumor development. We conclude by addressing promising opportunities for modulation of purinergic/adenosinergic signaling in the prevention and treatment of pancreatobiliary diseases, inclusive of cancer.

Radiofrequency ablation in combination with CD73 inhibitor AB680 reduces tumor growth and enhances anti-tumor immunity in a syngeneic model of pancreatic ductal adenocarcinoma

“…However, tumor growth curves showed a relapse in tumor progression by day 7 after treatment. KPC cells were recently described to produce ADO and express CD73 ( 20 ); thus, to assess whether RFA may be inducing resistant mechanisms during the acute phase in our preclinical model, we studied a very well-known pathway of TME immunosuppression ( 5 , 20 – 25 ) by determining by HPLC accumulation of AMP, ADO and INO. Our results revealed that ADO was being generated in RFA treated tumors during the acute phase as early as 4 days after treatment, where it was also found enriched in circulation when compared to Sham treated mice.…”

“…Adenosine (ADO) signaling has emerged as a key extracellular nucleoside signaling pathway involved in tumor immunity as it promotes severe immunosuppression when produced at high levels within the TME. ADO is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5′ ectonucleotidase (CD73) that catabolize ATP to adenosine ( 5 ). Additionally, once generated, extracellular ADO can be converted to inosine (INO) via an enzyme named adenosine deaminase (ADA) ( 6 ).…”

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

“…In the presence of ectonucleotidase triphosphate diphosphohydrolase-1 (CD39), a cell-surface enzyme with catalytic activity, ATP is rapidly converted to AMP, which is the substrate for catalytic conversion to adenosine by CD73. Preclinical models have shown targeting adenosine signaling has potent antitumor effects (12)(13)(14)(15)(16)(17)(18)(19).…”

CD73 ‐generated extracellular adenosine promotes resolution of neutrophil‐mediated tissue injury and restrains metaplasia in pancreatitis

“…Additionally, A 3 receptor affinity for adenosine was shown to rank higher than A 2B ; however, discrepancies in the role of A 3 receptors have also been observed in the literature, presenting both anti-inflammatory and pro-inflammatory effects. 44,[48][49][50][51][52][53][54] Therefore, at early stages of inflammation, low local concentrations of adenosine may promote immune recruitment via the A 1 receptor while later high adenosine concentrations can suppress immune activity via the A 2A , A 2B , or A 3 receptors. 44,52,55 Adenosine binding to adenosine receptors modulates both the innate and the adaptive immune response to hypoxia, inflammation, and tissue repair.…”

“…Additionally, A 3 receptor affinity for adenosine was shown to rank higher than A 2B ; however, discrepancies in the role of A 3 receptors have also been observed in the literature, presenting both anti‐inflammatory and pro‐inflammatory effects. 44 , 48 , 49 , 50 , 51 , 52 , 53 , 54 Therefore, at early stages of inflammation, low local concentrations of adenosine may promote immune recruitment via the A 1 receptor while later high adenosine concentrations can suppress immune activity via the A 2A , A 2B , or A 3 receptors. 44 , 52 , 55 …”