CD73 promotes colitis‑associated tumorigenesis in mice

Abstract

Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumorigenesis. A mouse model of colitis-associated tumorigenesis (CAT) induced by azoxymethane and dextran sulfate sodium was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumor formation were assessed macroscopically. Inflammatory cytokine measurement and RNA sequencing on colon tissues were performed. Inhibition of CD73 by adenosine 5'-(α,β-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumor number and smaller tumor size compared with the model group. Activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranur onamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced, while activation of adenosine receptors exacerbated, the histological damage of the colon. Increased expression of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to RNA sequencing results, potential oncogenes such as arachidonate 15-lipoxygenase (ALOX15), Bcl-2-like protein 15 (Bcl2l15) and N-acetylaspartate synthetase (Nat8l) were downregulated in the APCP group and upregulated in the NECA group compared with the model group. Therefore, inhibition of CD73 attenuated IBD-associated tumorigenesis, while activation of adenosine receptors exacerbated tumorigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.

CD73-positive cell spheroid transplantation attenuates colonic atrophy

“…These findings suggest that transplantation of CD73 + cells could lead to tumor formation. However, the promotion of colitis-associated tumorigenesis by CD73 reported by Liu et al was observed in a chronic inflammatory model generated following three cycles of treatment with azoxymethane, a genotoxic colonic carcinogen, and DSS administration for 3 weeks (Liu et al, 2020), which is different from the acute colitis model used in the present study. Moreover, transplanted MSCs disappear after temporary engraftment (Kean et al, 2013), but we will further investigate whether CD73 + cell spheroids remain at the injured site for a long time using longitudinal analysis, considering the potential clinical application of MSC transplantation.…”

“…Inhibition of CD73 activity or gene silencing in tumor cells is reported to attenuate tumorigenesis (Jin et al , 2010; Stagg et al , 2010). Additionally, CD73 is highly expressed in solid tumors and is reported to facilitate colitis-associated tumorigenesis (Liu et al , 2020; Roh et al , 2020). These findings suggest that transplantation of CD73 + cells could lead to tumor formation.…”

Characterization of Differential Expression Patterns of the Extracellular Purinergic Enzymes in Colorectal Cancer

“…Considering elevated purinergic signaling levels in colon cancer samples, we strongly suppose that purinergic ecto-enzymes can be responsible for a similar antiinflammatory/immunosuppressive role in colorectal tumorigenesis (X.-H. Liu et al 2020). Given their immunosuppressive powers, it would not be surprising to see that these proteins are highly expressed in the colorectal tumor microenvironment (Liu et al 2012).…”

“…While some studies associate stromal CD73 expression with higher tumorigenic potential in colorectal cancer (Wu et In CRC studies with the cell lines, tumor cell specific CD73 expression was found to be essential for tumor growth in vitro and in vivo (Wu et al 2016). However, in a colitis associated cancer model, use of CD73 specific inhibitor reduced the tumor burden (Liu et al 2020). On the contrary, another report suggested that tumor cell specific CD73 expression is dispensable for colorectal tumor growth while stroma specific (mesenchymal cells) CD73 expression was essential for CD73-driven tumor growth (Yu et al 2020).…”

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

“…In addition, concentrations of N-acetylaspartate produced by ovarian cancer cells were found to increase in parallel with cancer progression and correlated with, the polarization of macrophages towards the M2-like phenotype [156]. Non-specific stimulation of ARs by the agonist NECA upregulated the expression of NAT8L RNA in a colitis-associated tumorigenesis mouse model [157]. Because CD73 inhibitor conversely downregulated NAT8L expression, the observations were ascribed to AR modulation.…”