The Effects of Rage Signaling On the Development of Colorectal Liver Metastases
Joseph Dinorcia*, Nikalesh Ippagunta, Mark Foster, Dorota N. Moroziewicz, Jean C. Emond, Ann Marie Schmidt, John D. Allendorf
Surgery, Columbia University College of Physicians and Surgeons, New York, NY
Background The receptor for advanced glycation endproducts (RAGE) is a transmembrane protein implicated in tumor cell migration and invasion. RAGE expression in colorectal cancer increases with increasing Dukes’ stage. Purpose We hypothesized that RAGE signaling contributes importantly to the pathogenesis of metastases and that blocking the signaling pathway will reduce tumor development and growth in a mouse model of colorectal adenocarcinoma liver metastasis. Materials and Methods Balb/c mice (n=24) underwent portal vein injection with 2x104 CT26 colorectal adenocarcinoma cells (syngeneic). Mice received either daily intraperitoneal injections of 100 mcg sRAGE (the soluble extracellular component of the RAGE receptor used as a competitive inhibitor) or vehicle. C57Bl/6 mice (n=10 per group) underwent portal vein injection with 2x104 MC38 colorectal adenocarcinoma cells (syngeneic) that had been stably transfected with different RAGE constructs (full-length (FL), cytosolic tail-deleted (dominant negative (DN) cell surface competitive inhibitor), or mock transfectant (M)). RAGE null mice (C57Bl/6 background) and littermate controls (RAGE +/+) underwent portal vein injections with 2x104 MC38 wildtype cells (n=10 per group). Mice were sacrificed and evaluated in a blinded fashion on days 21 and 28 for tumor incidence, number of tumor nodules, and overall tumor burden. Data was analyzed using ANOVA followed by student t-test and chi square. Results Pharmacologic RAGE blockade with sRAGE significantly reduced the incidence of hepatic tumor nodule development (Day 21: 83.3% versus 16.7%, p<0.03), reduced the number of hepatic tumor nodules observed (Day 21: 2.2 +/- 1.7 nodules versus 0.17 +/- 0.41 nodules, p< 0.03; Day 28: 4.2 +/- 2.4 nodules versus 1.2 +/- 1.2 nodules, p<0.02), and reduced tumor burden (Day 21: 10.7 +/- 22.3 mg versus 0.0007 +/- 0.002 mg; Day 28: 256.8 +/- 198.6 mg versus 76.7 +/- 170.6 mg, p<0.05). Stable transfection of the tumor cells with functional FL RAGE resulted in significantly increased tumor burden when compared to cells transfected with dysfunctional DN RAGE (Day 28: 1330 +/- 1340 mg versus 271 +/- 252 mg, p<0.03). Tumor burden was significantly reduced in RAGE null mice compared to littermate controls (Day 28: 705 +/- 1293 mg versus 3442 +/- 1931 mg, p<0.002).Conclusion These data indicate that RAGE signaling plays an important role in the development of colorectal liver metastases. Further work is needed to evaluate the mechanism of these differences and to develop strategies that exploit RAGE signaling pathways as novel targets for therapeutic intervention.
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