apyrase and Pancreatic-Neoplasms

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, P2Y

Topics: 5'-Nucleotidase; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Apyrase; Carcinoma, Pancreatic Ductal; Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins; Humans; Immunotherapy; Pancreas; Pancreatic Neoplasms; Pancreatic Stellate Cells; Receptors, Adenosine A2; Receptors, Purinergic P2X7; Receptors, Purinergic P2Y12; Receptors, Purinergic P2Y2; Signal Transduction; Tumor Microenvironment

The ectonucleotidases CD39 and CD73 catalyze extracellular ATP to immunosuppressive adenosine, and as such, represent potential cancer targets. We investigated biological impacts of CD39 and CD73 in pancreatic ductal adenocarcinoma (PDAC) by studying clinical samples and experimental mouse tumors. Stromal CD39 and tumoral CD73 expression significantly associated with worse survival in human PDAC samples and abolished the favorable prognostic impact associated with the presence of tumor-infiltrating CD8+ T cells. In mouse transplanted KPC tumors, both CD39 and CD73 on myeloid cells, as well as CD73 on tumor cells, promoted polarization of infiltrating myeloid cells towards an M2-like phenotype, which enhanced tumor growth. CD39 on tumor-specific CD8+ T cells and pancreatic stellate cells also suppressed IFNγ production by T cells. Although therapeutic inhibition of CD39 or CD73 alone significantly delayed tumor growth in vivo, targeting of both ectonucleotidases exhibited markedly superior antitumor activity. CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Accordingly, large-scale pharmacogenomic analyses of human PDAC cell lines revealed significant associations between CD73 expression and gemcitabine chemoresistance. Strikingly, increased DNA damage in CD73-deficient tumor cells associated with activation of the cGAS-STING pathway. Moreover, cGAS expression in mouse KPC tumor cells was required for antitumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.

Topics: 5'-Nucleotidase; Adenosine; Animals; Apyrase; CD8-Positive T-Lymphocytes; Cell Line; Humans; Mice; Pancreatic Neoplasms

Chronic inflammation, fibrosis, atrophy, malignant transformation, and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (P2X7, P2Y2, and P2Y6) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2X7 mRNA upregulation was associated with chronic pancreatitis, and heightened protein expression was found to be localized to infiltrating cells. P2Y2 was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2X7, and P2Y2 infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases.

Topics: Adult; Alcoholism; Antigens, CD; Apyrase; Cell Transformation, Neoplastic; Chronic Disease; Female; Gene Expression Regulation; Humans; Inflammation; Male; Middle Aged; Neoplasm Staging; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Receptors, Purinergic P2; Thromboembolism; Tissue Donors

Elevated levels of extracellular ATP have been observed in many tumors. We have localized NTPDase1/CD39, one of the principal extracellular nucleotide-hydrolyzing enzymes, in normal and cancerous human pancreas. NTPDase/E-ATPDase activity was demonstrated with an enzyme histochemical technique on cryosections of human pancreas. Acinar and duct epithelial cells were devoid of E-ATPDase activity in both normal and transformed tissue. Endothelial cells and smooth muscle around blood vessels and larger ducts showed strong activity. Nerves, connective tissue, and the beta-cells of the islets were also stained. In cancerous tissue this activity was diminished in the smooth muscle around the ducts and was absent from newly formed connective tissue. Immunostaining for CD39 supported these results but revealed the presence of inactive CD39 in the duct epithelial cells. We hypothesize that the significantly diminished activity of NTPDase1 in the tissues surrounding the ducts may be associated with the processes that lead to tumor formation in human pancreas.

Topics: Adenosine Triphosphatases; Antigens, CD; Apyrase; Humans; Immunohistochemistry; Islets of Langerhans; Pancreas; Pancreatic Neoplasms

The mechanism leading to the hypercoagulability in pancreatic carcinoma is unclear. The rapid progress of the disease after its diagnosis and the inaccessibility of the tumor make studies on the mechanism difficult in man. With the successful induction of this malignancy and conversion of it into an ascites tumor in Syrian golden hamsters, interactions between isolated tumor cells and individual hemostatic components can be investigated. In this paper, studies on in vitro tumor cell-platelet interactions and some hemostatic changes in hamsters following intravenous injection of isolated tumor cells are described. Freshly isolated tumor cells and tumor-cell sonicates, but not those that had been kept at 4 or -70 C overnight, induced comparable aggregation of human platelets in both heparinized and citrated platelet-rich plasmas (hPRP and cPRP). The aggregation was not followed by clot formation; a specific synthetic thrombin inhibitor had no effect on the aggregation in either hPRP or cPRP. Washed and gel-filtered platelets, even in the presence of 5% of citrated or heparinized platelet-poor plasma (cPPP or hPPP) failed to be aggregated by tumor cells. Tumor-cell-induced platelet aggregation was accompanied by thromboxane formation and serotonin release, both of which were several orders of magnitude greater in cPPP than in hPRP. Aspirin, apyrase, and PGI2 all inhibited tumor-cell-induced platelet aggregation in both PRPs, but the inhibition by aspirin was minimal. Intravenous infusion of isolated tumor cells into normal hamsters resulted in a 50% reduction of platelet count and a 20-30% decline in antithrombin III and fibrinogen. Platelet aggregates and fibrin strands were seen in the lungs of these animals.

Topics: Animals; Antithrombin III; Apyrase; Ascites; Aspirin; Blood Coagulation; Blood Platelets; Cricetinae; Epoprostenol; Fibrinogen; Humans; Mesocricetus; Microscopy, Electron; Pancreatic Neoplasms; Platelet Aggregation; Platelet Count; Serotonin; Thromboxane B2