Analyse der Rolle der B Zellen im sporadischen und Kolitis-assoziiertem Kolonkarzinom
Zusammenfassung der Projektergebnisse
Patients with inflammatory bowel diseases are at increased risk of developing colitisassociated colorectal cancer (CAC). Chronic inflammation is a hallmark of many cancers as it facilitates the development of neoplastic cells by creating a pro-tumoral milieu. By using B celldeficient mice (JHT-/-), we could demonstrate that B cells play a key role in the development of CAC in the AOM/DSS model, since JHT-/- mice were completely tumour-resistant. Reconstitution of JHT-/- mice by an adoptive B cell-transfer of wildtype (WT) CD19+ splenocytes prior to AOM/DSS treatment restored tumour growth in these mice. Analysis of the inflammation phase (day 14) between WT and JHT-/- mice revealed that the absence of B cells results in decreased accumulation of immune cells, mainly pathogenic Th1 and Th17 cells, in the colonic lamina propria (LP) and reduced levels of pro-inflammatory cytokines, such as Il6, Il1ß, and Il17, hereby preventing the establishment of a proinflammatory milieu that promotes tumorigenesis. The more severe colitis in WT animals required increased regeneration of the intestinal epithelium, as evidenced by a higher number of proliferating (Ki67+) epithelial cells compared to JHT-/- animals. Exacerbated activation of proliferation both stimulates the repair of the epithelium but also the growth of AOM-induced mutagenic cells, which may explain the tumour resistance seen in the less-inflamed JHT-/- animals. We could not confirm a role of B cells as antibody-secreting cells in the development of CAC, although antibody levels were elevated in WT animals during inflammation as well as in tumorous tissue. Antibody-deficient IgMi mice showed the same tumour burden as WT mice. We wanted to find out whether B cells exert a regulatory function in CAC by secreting IL-10, similarly to IL-10 producing Treg cells, which are known to exert immunosuppressive and tumour promoting properties. Although mice lacking IL- 10 in B cells (IL-10BKO mice) display similar DSS-driven inflammation as control mice, tumour progression was significantly reduced compared to littermate controls, indicated by a reduced tumour number and tumour size. Analysis of tumorous tissue revealed that loss of B-cell-specific IL-10 largely prevented the activation of pro-tumoral M2-macrophages, as evidenced by markedly reduced expression of the M2-specific marker arginase 1 (Arg1) as well as the mannose receptor CD206. Thus, impaired M2-macrophage activation could impede CAC tumour progression in IL-10BKO mice. In conclusion, we demonstrated that B cells influence the severity of DSS inflammation in the AOM/DSS model and thus promote the initiation of CAC. Furthermore, our data indicate that IL-10-secreting B cells promote tumor progression. This indicates that there is not only one B-cell-associated mechanism leading to the development of CAC, but rather it is a combination of multiple factors.
Projektbezogene Publikationen (Auswahl)
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Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment. Nature Communications, 9(1).
Wunderlich, Claudia M.; Ackermann, P. Justus; Ostermann, Anna Lena; Adams-Quack, Petra; Vogt, Merly C.; Tran, My-Ly; Nikolajev, Alexei; Waisman, Ari; Garbers, Christoph; Theurich, Sebastian; Mauer, Jan; Hövelmeyer, Nadine & Wunderlich, F. Thomas
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Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis. Gastroenterology, 156(3), 692-707.e7.
Tang, Yilang; Reissig, Sonja; Glasmacher, Elke; Regen, Tommy; Wanke, Florian; Nikolaev, Alexei; Gerlach, Katharina; Popp, Vanessa; Karram, Khalad; Fantini, Massimo C.; Schattenberg, Jörn M.; Galle, Peter R.; Neurath, Markus F.; Weigmann, Benno; Kurschus, Florian C.; Hövelmeyer, Nadine & Waisman, Ari
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Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo. Archives of Toxicology, 95(7), 2507-2522.
Seiwert, Nina; Adam, Janine; Steinberg, Pablo; Wirtz, Stefan; Schwerdtle, Tanja; Adams-Quack, Petra; Hövelmeyer, Nadine; Kaina, Bernd; Foersch, Sebastian & Fahrer, Jörg
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B cell expansion hinders the stroma-epithelium regenerative cross talk during mucosal healing. Immunity, 55(12), 2336-2351.e12.
Frede, Annika; Czarnewski, Paulo; Monasterio, Gustavo; Tripathi, Kumar P.; Bejarano, David A.; Ramirez, Flores Ricardo O.; Sorini, Chiara; Larsson, Ludvig; Luo, Xinxin; Geerlings, Laura; Novella-Rausell, Claudio; Zagami, Chiara; Kuiper, Raoul; Morales, Rodrigo A.; Castillo, Francisca; Hunt, Matthew; Mariano, Livia Lacerda; Hu, Yue O.O.; Engblom, Camilla ... & Villablanca, Eduardo J.
