Abstract 4082: Contrasting role for claudin-2 in colitis-associated cancer (CAC) and spontaneous colon tumorigenesis (CRC) by regulating mucosal healing
Authors: Ahmad Rizwan , Kumar Balawant , Kumar Narendra , Washington Mary K. , Dhawan Punita , Singh Amar B. 
Published: August 2018

A link between chronic inflammation and colon cancer has long been appreciated. Accordingly, patients with ulcerative colitis are at higher risk for developing colitis-associated cancer (CAC). Mucosal barrier dysregulation allies with inflammation and colon cancer. Accordingly, claudin-2, a tight junction protein, is upregulated in ulcerative colitis, CAC and spontaneous colon cancer (CRC). Remarkably, claudin-2 expression is restricted to the colon crypt base, among undifferentiated and proliferative colonocytes, and its increased expression is responsible for the regulation of paracellular permeability, differentiation and proliferation. However, causal role of claudin-2 in CAC and CRC remains unclear. Considering the recent data from our laboratory and of others, that in vivo genetic manipulation of claudin-2 has inverse effects on colitis, we hypothesized an adaptive role for increased claudin-2 expression in colitis by promoting mucosal healing. We further postulated that mucosal healing can manifest in contrasting phenotypes for the CAC and CRC. To examine, Villin-claudin-2 transgenic (Cldn-2) mice were subjected to CAC by exposing them to AOM/DSS-induced cancer or interbred with the APCmin mice, the mouse model of spontaneous intestinal cancer. It was intriguing that the inflammation-driven colon cancer (AOM/DSS induced colon cancer) was significantly suppressed in Cldn-2 mice compared to WT littermates (p&lt;0.001). These mice also showed immune suppressive milieu ideal for spontaneous colon tumorigenesis. Accordingly, we found contrasting disparity in results from APCmin/Cldn-2 mice, generated by the cross between Cldn-2 and APCmin mice. These mice showed significant increase in intestinal tumor burden (248+40%, p&lt;0.001) and colonic tumor burden [Incidence (172.50±18%, p&lt;0.001) and size (521.5±34%, p&lt;0.001)] compared to APCmin mice. H&E analysis confirmed aggressive phenotype of APCmin-Cldn-2 mice tumors (vs APCmin mice tumors). APCmin/Cldn-2 mice also survived less than the APCmin mice. Further, inflammation induction by subjecting these mice to Dextran Sodium Sulfate (DSS) resulted in precocious colonic tumorigenesis only in APCmin mice, rejecting a role for the pro-inflammatory signaling in colon cancer progression in APCmin/Cldn-2 mice. High throughput transcriptome and oncogenic array analyses further suggested modifications of the key inflammatory and oncogenic signaling, in supporting these disparate phenotypes. Taken together, our data provide strong support for the key significance for the context and diverse immunogenic signaling in regulating CAC versus CRC. These studies also suggest that claudin-2 manipulated mice can provide the much needed mouse modelling to help identify key immunogenic signaling supportive of the colon tumorigenesis for therapeutic gains.

Citation Format: Rizwan Ahmad, Balawant Kumar, Narendra Kumar, Mary K. Washington, Punita Dhawan, Amar B. Singh. Contrasting role for claudin-2 in colitis-associated cancer (CAC) and spontaneous colon tumorigenesis (CRC) by regulating mucosal healing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4082.