CD73 promotes colitis‑associated tumorigenesis in mice

Liu,Xuan‑Hui; Wu,Xian‑Rui; Lan,Nan; Zheng,Xiao‑Bin; Zhou,Chi; Hu,Tuo; Chen,Yu‑Feng; Cai,Ze‑Rong; Chen,Ze‑Xian; Lan,Ping; Wu,Xiao‑Jian

doi:10.3892/ol.2020.11670

CD73 promotes colitis‑associated tumorigenesis in mice

Authors:
- Xuan‑Hui Liu
- Xian‑Rui Wu
- Nan Lan
- Xiao‑Bin Zheng
- Chi Zhou
- Tuo Hu
- Yu‑Feng Chen
- Ze‑Rong Cai
- Ze‑Xian Chen
- Ping Lan
- Xiao‑Jian Wu
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Affiliations: Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510655, P.R. China
Published online on: May 22, 2020 https://doi.org/10.3892/ol.2020.11670
Pages: 1221-1230
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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‑ribofuranuronamide (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.

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1	Liu TC and Stappenbeck TS: Genetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol. 11:127–148. 2016. View Article : Google Scholar : PubMed/NCBI
2	Khor B, Gardet A and Xavier RJ: Genetics and pathogenesis of inflammatory bowel disease. Nature. 474:307–317. 2011. View Article : Google Scholar : PubMed/NCBI
3	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI
4	Singh R, Mishra MK and Aggarwal H: Inflammation, immunity, and cancer. Mediators Inflamm. 2017:60273052017. View Article : Google Scholar : PubMed/NCBI
5	Navaneethan U, Zhu X, Lourdusamy D, Lourdusamy V, Shen B and Kiran R: Colorectal cancer resection rates in patients with inflammatory bowel disease: A population-based study. Gastroenterol Rep (Oxf). 6:263–269. 2018. View Article : Google Scholar : PubMed/NCBI
6	Bopanna S, Ananthakrishnan AN, Kedia S, Yajnik V and Ahuja V: Risk of colorectal cancer in Asian patients with ulcerative colitis: A systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2:269–276. 2017. View Article : Google Scholar : PubMed/NCBI
7	Lutgens MW, van Oijen MG, van der Heijden GJ, Vleggaar FP, Siersema PD and Oldenburg B: Declining risk of colorectal cancer in inflammatory bowel disease: An updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis. 19:789–799. 2013. View Article : Google Scholar : PubMed/NCBI
8	Zimmermann H: 5′-Nucleotidase: Molecular structure and functional aspects. Biochem J. 285((Pt 2)): 345–365. 1992. View Article : Google Scholar : PubMed/NCBI
9	Haskó G and Cronstein BN: Adenosine: An endogenous regulator of innate immunity. Trends Immunol. 25:33–39. 2004. View Article : Google Scholar : PubMed/NCBI
10	Antonioli L, Yegutkin GG, Pacher P, Blandizzi C and Haskó G: Anti-CD73 in cancer immunotherapy: Awakening new opportunities. Trends Cancer. 2:95–109. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhang B: CD73: A novel target for cancer immunotherapy. Cancer Res. 70:6407–6411. 2010. View Article : Google Scholar : PubMed/NCBI
12	Ghalamfarsa G, Kazemi MH, Raoofi Mohseni S, Masjedi A, Hojjat-Farsangi M, Azizi G, Yousefi M and Jadidi-Niaragh F: CD73 as a potential opportunity for cancer immunotherapy. Expert Opin Ther Targets. 23:127–142. 2019. View Article : Google Scholar : PubMed/NCBI
13	Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, Dwyer KM and Smyth MJ: Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci USA. 107:1547–1552. 2010. View Article : Google Scholar : PubMed/NCBI
14	Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, Shin T, Curiel TJ and Zhang B: CD73 on tumor cells impairs antitumor T-cell responses: A novel mechanism of tumor-induced immune suppression. Cancer Res. 70:2245–2255. 2010. View Article : Google Scholar : PubMed/NCBI
15	Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK and Smyth MJ: CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 71:2892–2900. 2011. View Article : Google Scholar : PubMed/NCBI
16	Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ and Zhang B: CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest. 121:2371–2382. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kaku H, Cheng KF, Al-Abed Y and Rothstein TL: A novel mechanism of B cell-mediated immune suppression through CD73 expression and adenosine production. J Immunol. 193:5904–5913. 2014. View Article : Google Scholar : PubMed/NCBI
18	Grenz A, Zhang H, Eckle T, Mittelbronn M, Wehrmann M, Köhle C, Kloor D, Thompson LF, Osswald H and Eltzschig HK: Protective role of ecto-5′-nucleotidase (CD73) in renal ischemia. J Am Soc Nephrol. 18:833–845. 2007. View Article : Google Scholar : PubMed/NCBI
19	Eckle T, Krahn T, Grenz A, Köhler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K and Eltzschig HK: Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation. 115:1581–1590. 2007. View Article : Google Scholar : PubMed/NCBI
20	Mahamed DA, Toussaint LE and Bynoe MS: CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection. Infect Immun. 83:721–729. 2015. View Article : Google Scholar : PubMed/NCBI
21	Ray MA, Johnston NA, Verhulst S, Trammell RA and Toth LA: Identification of markers for imminent death in mice used in longevity and aging research. J Am Assoc Lab Anim Sci. 49:282–288. 2010.PubMed/NCBI
22	Yang X, Zhang F, Wang Y, Cai M, Wang Q, Guo Q, Li Z and Hu R: Oroxylin A inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 signaling pathway. Inflamm Bowel Dis. 19:1990–2000. 2013.PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Kleinstein SE, Heath L, Makar KW, Poole EM, Seufert BL, Slattery ML, Xiao L, Duggan DJ, Hsu L, Curtin K, et al: Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia. Genes Chromosomes Cancer. 52:437–449. 2013. View Article : Google Scholar : PubMed/NCBI
25	Xiao R, Li C and Chai B: miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1. Biomed Pharmacother. 74:138–144. 2015. View Article : Google Scholar : PubMed/NCBI
26	Zand B, Previs RA, Zacharias NM, Rupaimoole R, Mitamura T, Nagaraja AS, Guindani M, Dalton HJ, Yang L, Baddour J, et al: Role of increased n-acetylaspartate levels in cancer. J Natl Cancer Inst. 108:djv4262016. View Article : Google Scholar : PubMed/NCBI
27	Torres J, Mehandru S, Colombel JF and Peyrin-Biroulet L: Crohn's disease. Lancet. 389:1741–1755. 2017. View Article : Google Scholar : PubMed/NCBI
28	Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L and Colombel JF: Ulcerative colitis. Lancet. 389:1756–1770. 2017. View Article : Google Scholar : PubMed/NCBI
29	Farraye FA, Odze RD, Eaden J and Itzkowitz SH: AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 138:746–774, 774.e1-4; quiz e12-13. 2010. View Article : Google Scholar : PubMed/NCBI
30	Askling J, Dickman PW, Karlén P, Broström O, Lapidus A, Löfberg R and Ekbom A: Colorectal cancer rates among first-degree relatives of patients with inflammatory bowel disease: A population-based cohort study. Lancet. 357:262–266. 2001. View Article : Google Scholar : PubMed/NCBI
31	Fumery M, Dulai PS, Gupta S, Prokop LJ, Ramamoorthy S, Sandborn WJ and Singh S: Incidence, risk factors, and outcomes of colorectal cancer in patients with ulcerative colitis with low-grade dysplasia: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 15:665–674.e5. 2017. View Article : Google Scholar : PubMed/NCBI
32	Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, Lofberg R, Brostrom O and Hellers G: Colorectal cancer in ulcerative colitis: A cohort study of primary referrals from three centres. Gut. 29:206–217. 1988. View Article : Google Scholar : PubMed/NCBI
33	Munkholm P, Langholz E, Davidsen M and Binder V: Intestinal cancer risk and mortality in patients with Crohn's disease. Gastroenterology. 105:1716–1723. 1993. View Article : Google Scholar : PubMed/NCBI
34	Rogler G: Chronic ulcerative colitis and colorectal cancer. Cancer Lett. 345:235–241. 2014. View Article : Google Scholar : PubMed/NCBI
35	Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, Oshima M, Fujii C and Mukaida N: Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest. 118:560–570. 2008.PubMed/NCBI
36	Azer SA: Overview of molecular pathways in inflammatory bowel disease associated with colorectal cancer development. Eur J Gastroenterol Hepatol. 25:271–281. 2013. View Article : Google Scholar : PubMed/NCBI
37	Taniguchi K and Karin M: IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 26:54–74. 2014. View Article : Google Scholar : PubMed/NCBI
38	Regateiro FS, Cobbold SP and Waldmann H: CD73 and adenosine generation in the creation of regulatory microenvironments. Clin Exp Immunol. 171:1–7. 2013. View Article : Google Scholar : PubMed/NCBI
39	Alam MS, Kuo JL, Ernst PB, Derr-Castillo V, Pereira M, Gaines D, Costales M, Bigley E and Williams K: Ecto-5′-nucleotidase (CD73) regulates host inflammatory responses and exacerbates murine salmonellosis. Sci Rep. 4:44862014. View Article : Google Scholar : PubMed/NCBI
40	Doherty GA, Bai A, Hanidziar D, Longhi MS, Lawlor GO, Putheti P, Csizmadia E, Nowak M, Cheifetz AS, Moss AC and Robson SC: CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease. Eur J Immunol. 42:3062–3072. 2012. View Article : Google Scholar : PubMed/NCBI
41	Forte G, Sorrentino R, Montinaro A, Luciano A, Adcock IM, Maiolino P, Arra C, Cicala C, Pinto A and Morello S: Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. J Immunol. 189:2226–2233. 2012. View Article : Google Scholar : PubMed/NCBI
42	Zhu Y, Gu L, Li Y, Lin X, Shen H, Cui K, Chen L, Zhou F, Zhao Q, Zhang J, et al: miR-148a inhibits colitis and colitis-associated tumorigenesis in mice. Cell Death Differ. 24:2199–2209. 2017. View Article : Google Scholar : PubMed/NCBI
43	Odashima M, Bamias G, Rivera-Nieves J, Linden J, Nast CC, Moskaluk CA, Marini M, Sugawara K, Kozaiwa K, Otaka M, et al: Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology. 129:26–33. 2005. View Article : Google Scholar : PubMed/NCBI
44	Sotnikov I and Louis NA: CD73-dependent regulation of interferon alphaA and interleukin-10 in the inflamed mucosa. ScientificWorldJournal. 10:2167–2180. 2010. View Article : Google Scholar : PubMed/NCBI
45	Mantzaris GJ: Previous cancer and/or lymphoma in patients with refractory IBD-con: Anti-TNF or conventional immunosuppressive treatment. Dig Dis. 32 (Suppl 1):S122–S127. 2014. View Article : Google Scholar
46	Bandzar S, Gupta S and Platt MO: Crohn's disease: A review of treatment options and current research. Cell Immunol. 286:45–52. 2013. View Article : Google Scholar : PubMed/NCBI
47	Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI
48	Namgaladze D, Snodgrass RG, Angioni C, Grossmann N, Dehne N, Geisslinger G and Brüne B: AMP-activated protein kinase suppresses arachidonate 15-lipoxygenase expression in interleukin 4-polarized human macrophages. J Biol Chem. 290:24484–24494. 2015. View Article : Google Scholar : PubMed/NCBI