Alternatively activated macrophages cause DNA damage through an arginase 1-mediated bystander effect and promote epithelial cell transformation

Posted by AweSamo April 3, 2026
Alternatively activated macrophages cause DNA damage through an arginase 1-mediated bystander effect and promote epithelial cell transformation

  • McLean MH, Murray GI, Stewart KN, Norrie G, Mayer C, Hold GL, et al. The inflammatory microenvironment in colorectal neoplasia. PLoS One. 2011;6:e15366.


    Google Scholar     

  • Lasry A, Zinger A, Ben-Neriah Y. Inflammatory networks underlying colorectal cancer. Nat Immunol. 2016;17:230–40.


    Google Scholar     

  • Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell. 2013;24:242–56.


    Google Scholar     

  • Aran D, Lasry A, Zinger A, Biton M, Pikarsky E, Hellman A, et al. Widespread parainflammation in human cancer. Genome Biol. 2016;17:145.


    Google Scholar     

  • Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, et al. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res. 1998;58:334–41.


    Google Scholar     

  • Chapple KS, Cartwright EJ, Hawcroft G, Tisbury A, Bonifer C, Scott N, et al. Localization of cyclooxygenase-2 in human sporadic colorectal adenomas. Am J Pathol. 2000;156:545–53.


    Google Scholar     

  • Szylberg L, Janiczek M, Popiel A, Marszalek A. Expression of COX-2, IL-1b, TNF-a and IL-4 in epithelium of serrated adenoma, adenoma and hyperplastic polyp. Arch Med Sci. 2016;12:172–8.


    Google Scholar     

  • Jang TJ, Kim SA, Kim MK. Increased number of arginase 1-positive cells in the stroma of carcinomas compared to precursor lesions and nonneoplastic tissues. Pathol Res Pr. 2018;214:1179–84.


    Google Scholar     

  • Song J, Kim D, Jung J, Choi E, Lee Y, Jeong Y, et al. Elucidating immunological characteristics of the adenoma-carcinoma sequence in colorectal cancer patients in South Korea using a bioinformatics approach. Sci Rep. 2024;14:10105.


    Google Scholar     

  • Shin AE, Tesfagiorgis Y, Larsen F, Derouet M, Zeng PYF, Good HJ, et al. F4/80+Ly6Chigh macrophages lead to cell plasticity and cancer initiation in colitis. Gastroenterology. 2023;164:593–609.


    Google Scholar     

  • Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906.


    Google Scholar     

  • Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15:1016–22.


    Google Scholar     

  • Slowicka K, Petta I, Blancke G, Hoste E, Dumas E, Sze M, et al. Zeb2 drives invasive and microbiota-dependent colon carcinoma. Nat Cancer. 2020;1:620–34.


    Google Scholar     

  • Popivanova BK, Kostadinova FI, Furuichi K, Shamekh MM, Kondo T, Wada T, et al. Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res. 2009;69:7884–92.


    Google Scholar     

  • Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S, et al. The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis. Mucosal Immunol. 2017;10:421–33.


    Google Scholar     

  • Yang Y, Wang X, Huycke T, Moore DR, Lightfoot SA, Huycke MM. Colon macrophages polarized by commensal bacteria cause colitis and cancer through the bystander effect. Transl Oncol. 2013;6:596–606.


    Google Scholar     

  • Gu T, Li Q, Egilmez NK. IFNb-producing CX3CR1+ macrophages promote T-regulatory cell expansion and tumor growth in the APCmin/+/Bacteroides fragilis colon cancer model. Oncoimmunology. 2019;8:e1665975.


    Google Scholar     

  • Bader JE, Enos RT, Velazquez KT, Carson MS, Nagarkatti M, Nagarkatti PS, et al. Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer. Am J Physiol Gastrointest Liver Physiol. 2018;314:G22–G31.


    Google Scholar     

  • Wang X, Allen TD, May RJ, Lightfoot S, Houchen CW, Huycke MM. Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res. 2008;68:9909–17.


    Google Scholar     

  • Wang X, Allen TD, Yang Y, Moore DR, Huycke MM. Cyclooxygenase-2 generates the endogenous mutagen trans-4-hydroxy-2-nonenal in Enterococcus faecalis-infected macrophages. Cancer Prev Res (Philos). 2013;6:206–16.


    Google Scholar     

  • Wang X, Huycke MM. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology. 2007;132:551–61.


    Google Scholar     

  • Wang X, Yang Y, Moore DR, Nimmo SL, Lightfoot SA, Huycke MM. 4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages. Gastroenterology. 2012;142:543–51.


    Google Scholar     

  • Yang Y, Wang X, Moore DR, Lightfoot SA, Huycke MM. TNF-a mediates macrophage-induced bystander effects through netrin-1. Cancer Res. 2012;72:5219–29.


    Google Scholar     

  • Zhou H, Ivanov VN, Gillespie J, Geard CR, Amundson SA, Brenner DJ, et al. Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway. Proc Natl Acad Sci USA. 2005;102:14641–6.


    Google Scholar     

  • Lorimore SA, Chrystal JA, Robinson JI, Coates PJ, Wright EG. Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation. Cancer Res. 2008;68:8122–6.


    Google Scholar     

  • Emerit I, Garban F, Vassy J, Levy A, Filipe P, Freitas J. Superoxide-mediated clastogenesis and anticlastogenic effects of exogenous superoxide dismutase. Proc Natl Acad Sci USA. 1996;93:12799–804.


    Google Scholar     

  • Emerit I, Khan SH, Esterbauer H. Hydroxynonenal, a component of clastogenic factors? Free Radic Biol Med. 1991;10:371–7.


    Google Scholar     

  • Wang X, Yang Y, Huycke MM. Commensal bacteria drive endogenous transformation and tumour stem cell marker expression through a bystander effect. Gut. 2015;64:459–68.


    Google Scholar     

  • Wang X, Yang Y, Huycke MM. Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis. Oncotarget. 2017;8:102176–90.


    Google Scholar     

  • Katsube T, Mori M, Tsuji H, Shiomi T, Wang B, Liu Q, et al. Most hydrogen peroxide-induced histone H2AX phosphorylation is mediated by ATR and is not dependent on DNA double-strand breaks. J Biochem. 2014;156:85–95.


    Google Scholar     

  • Kopp B, Khoury L, Audebert M. Validation of the gH2AX biomarker for genotoxicity assessment: a review. Arch Toxicol. 2019;93:2103–14.


    Google Scholar     

  • Sahin E, Haubenwallner S, Kuttke M, Kollmann I, Halfmann A, Dohnal AM, et al. Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J Immunol. 2014;193:1717–27.


    Google Scholar     

  • Rotondo R, Barisione G, Mastracci L, Grossi F, Orengo AM, Costa R, et al. IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer. 2009;125:887–93.


    Google Scholar     

  • Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: a multifaceted enzyme important in health and disease. Physiol Rev. 2018;98:641–65.


    Google Scholar     

  • Roberts PJ, Riley GP, Morgan K, Miller R, Hunter JO, Middleton SJ. The physiological expression of inducible nitric oxide synthase (iNOS) in the human colon. J Clin Pathol. 2001;54:293–7.


    Google Scholar     

  • O’Carroll C, Fagan A, Shanahan F, Carmody RJ. Identification of a unique hybrid macrophage-polarization state following recovery from lipopolysaccharide tolerance. J Immunol. 2014;192:427–36.


    Google Scholar     

  • Witherel CE, Sao K, Brisson BK, Han B, Volk SW, Petrie RJ, et al. Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages. Biomaterials. 2021;https://doi.org/10.1016/j.biomaterials.2021.120667.

  • Coates PJ, Rundle JK, Lorimore SA, Wright EG. Indirect macrophage responses to ionizing radiation: implications for genotype-dependent bystander signaling. Cancer Res. 2008;68:450–6.


    Google Scholar     

  • Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Med Inflamm. 2015;2015:816460.


    Google Scholar     

  • Gerner EW, Bruckheimer E, Cohen A. Cancer pharmacoprevention: targeting polyamine metabolism to manage risk factors for colon cancer. J Biol Chem. 2018;293:18770–8.


    Google Scholar     

  • Burke CA, Dekker E, Lynch P, Samadder NJ, Balaguer F, Huneburg R, et al. Eflornithine plus sulindac for prevention of progression in familial adenomatous polyposis. N Engl J Med. 2020;383:1028–39.


    Google Scholar     

  • Meyskens FL Jr., McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Philos). 2008;1:32–8.


    Google Scholar     

  • Balaguer F, Stoffel EM, Burke CA, Dekker E, Samadder NJ, Van Cutsem E, et al. Combination of sulindac and eflornithine delays the need for lower gastrointestinal surgery in patients with familial adenomatous polyposis: post hoc analysis of a randomized clinical trial. Dis Colon Rectum. 2022;65:536–45.


    Google Scholar     

  • Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol. 2006;176:2085–94.


    Google Scholar     

  • Wright PB, McDonald E, Bravo-Blas A, Baer HM, Heawood A, Bain CC, et al. The mannose receptor (CD206) identifies a population of colonic macrophages in health and inflammatory bowel disease. Sci Rep. 2021;11:19616.


    Google Scholar     

  • Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–88.


    Google Scholar     

  • Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE, van den Berg SM, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016;17:684–96.


    Google Scholar     

  • Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70:46–58.


    Google Scholar     

  • Parodi B, Aresu O, Bini D, Lorenzini R, Schena F, Visconti P, et al. Species identification and confirmation of human and animal cell lines: a PCR-based method. Biotechniques. 2002;32:432–4.


    Google Scholar     

  • Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67:93–9.


    Google Scholar     

    • Tags: