Recent studies have revealed the importance of colonic inflammation for CRC development. Multiple epidemiologic studies have linked the risk of CRC occurrence, prognosis and survival with obesity-associated metabolic dysfunction. Furthermore, recent studies suggest that neutrophils play an indispensable role in the initiation/progression of CRC. Inflammatory neutrophils produce serine proteinases (NSPs), of which activity is involved in the pathogenesis of neutrophil-dependent inflammation and progression of chronic inflammatory diseases, particularly development of IBD and progression of colitis associated-colon cancer (CAC). In preliminary studies, we have demonstrated that IGFBP-3 exerts both antitumor and anti-inflammatory functions through the newly identified IGFBP-3 receptor (IGFBP-3R) in a variety of cancers including CRC. We have identified that the NSPs are IGFBP-3 specific proteases and that significant increase of their activity with IGFBP-3 proteolysis in circulation is observed in chronic inflammatory conditions. Thus, in light of data confirming neutrophil activation in the setting of colonic inflammation and our data suggesting that NSPs increase IGFBP-3 proteolysis, the novel NSP-IGFBP-3/IGFBP-3R system may play a critical role in CAC development. Furthermore, our in vivo preliminary data validates critical role of IGFBP-3/IGFBP-3R signaling in CAC development showing that IGFBP-3R agonistic monoclonal antibody (mAb) inhibits CAC development in AOM/DSS CAC mice via induction of apoptosis and suppression of tumor-activated NF-?B signaling. This translational research proposal will test the hypothesis that colitis-induced activation of NSPs leads to CAC through increased production/activity of proinflammatory/immunomodulatory effectors and decreased level of intact biologically-active IGFBP-3 in circulation and in colon tissue. Moreover, we hypothesize NSP inhibitors would reduce colonic inflammation and CAC development via suppression of proinflammatory signaling and NSP-induced IGFBP-3 proteolysis as well. We propose to 1) examine the effect of NSPs and NSP inhibitors on production/activity of proinflammatory/immunomodulatory effectors and the anti- inflammatory/antiproliferative actions of IGFBP-3/IGFBP-3R signaling in vitro; and 2) determine if NSP inhibitors inhibit progression of CRC in lean and obese CAC mouse models. In summary, this proposal is designed to test a novel idea that 1) Aralast (AAT) and the novel small peptide inhibitor as preventive and/or therapeutic interventions for CAC; 2) IGFBP-3, NSPs and specific cytokines (TNF-a, IL-6 etc.) as potential diagnostic/prognostic biomarkers; and 3) the AAT-NSP-IGFBP-3/IGFBP-3R axis as therapeutic targets using two well-established CAC mouse models. The results of this study will allow us to initiate further clinical trials to establish efficacy and optimal dosing of Aralast to CAC patients. We also strongly believe that the findings should allow us to pursue the IGFBP-3R agonistic mAbs as a targeted pharmacotherapy using human/mouse bioluminescent orthotopic CRC athymic/syngeneic mouse systems.
One of the paradigm shifts in colorectal cancer (CRC) research describes that colonic inflammation may contribute to tumorigenesis and progression of CRC. Recent studies demonstrate that antitumor and anti-inflammatory IGFBP-3 is degraded (proteolyzed) into smaller fragments in chronic inflammatory conditions, which may contribute to CRC development in patients with inflammatory bowel diseases. Through a combination of integrated laboratory and animal experiments, this research proposal will identify diagnostic/prognostic biomarkers, therapeutic potential of AAT and a small peptide for chronic colitis-associated CRC, and new anti-inflammatory/antitumor signaling cascade neutrophil serine protease (NSP)- IGFBP-3/IGFBP-3 receptor axis in CRC.
