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Studies suggest that certain immune-mediated diseases may be associated with cancer risk beyond local organs. Prolonged systemic inflammation from inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) pose a greater risk to colorectal cancer (CRC) and accumulating data suggests that prostate cancer (PCa) risk is higher in patients with UC but not CD and that patients with PCa may be at a greater risk for CRC. A better understanding of the biological interactions between these conditions could have important implications for cancer screening, detection, and prevention in high-risk populations. However, data to establish the relationships and relative contributions of these diseases are lacking. Here, we explored these relationships using preclinical mouse models of dextran sulfate sodium (DSS)-induced colitis (DSS-UC) and DSS/azoxymethane (AOM)-induced CRC (DSS/AOM-CRC) in young and aged healthy wildtype mice and transgenic mice harboring Pten-deficient PCa. In the DSS/AOM-CRC model, aged PCa-bearing conditional Pten-knockout (KO) mice experienced poorer overall survival compared to age-matched wildtype (WT) without PCa because of CRC. DSS/AOM-CRC incidence was not affected by the presence of PCa, however tumor burden was higher in KO mice compared to WT and in KO mice, DSS/AOM-CRC accelerated PCa growth and progression. Prostates from WT DSS/AOM-CRC mice showed higher incidence of hyperplasia and greater myeloid cell infiltration compared to healthy controls. Systemic changes associated with DSS/AOM-CRC in both WT and KO mice included splenomegaly, lymphadenopathy, and immune cell composition. The impact of DSS-UC was investigated conditional Pten/Trp53-double knockout (DKO) mice with DDS only treatments starting at an age prior to the development of PCa. In this setting, cycling DSS led to the development of UC after 10 weeks of treatment and accelerated prostate tumor development characterized by high grade prostatic intraepithelial neoplasia (PIN) grade dysplasia and increased cell proliferation. Prostate tumors from mice with DSS-UC exhibited an altered tumor immune microenvironment characterized by a higher degree of inflammatory cell infiltrate. Changes in immune cell composition were also observed in peripheral blood and secondary lymphoid organs. These preclinical models recapitulated disease relationships observed in humans and provide a platform to further investigate biological mechanisms and therapeutic interventions. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Shogo Adomi, Eri Banno, Yasunori Mori, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Exploring the relationships between prostate cancer, colorectal cancer, and ulcerative colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 640. |
