Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP

Abstract

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immunebased diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. Despite these findings, the role of the endogenous peptide in regulating immune function is unknown. To determine if endogenous PACAP plays a protective role in inflammatory bowel disease (IBD) and IBD-associated colorectal cancer in mice, PACAP-deficient (KO) mice were subjected to 3 cycles of dextran sulfate sodium (DSS) in drinking water over 2 months, an established mouse model for colitis. Compared to wild type (WT) controls, PACAP KO mice exhibited more severe clinical symptoms of colitis and had significantly higher colonic inflammation on pathological examination. Moreover, 60% of the PACAP KO mice developed colorectal tumors with an aggressive-appearing pathology. Consistent with published data, DSS-treated WT mice did not develop such tumors. The results demonstrate a new mouse model which rapidly develops inflammation-associated colorectal cancer in the absence of a carcinogen. ' 2007 Wiley-Liss, Inc.Key words: pituitary adenylyl cyclase activating peptide (PACAP); inflammation; colorectal cancer; colitis; cancer Chronic inflammatory diseases are known to be linked to the development of cancer.1 In one of the more prominent examples, colorectal cancer (CRC) occurs at a significantly higher rate in patients with inflammatory bowel disease (IBD) compared to the normal population. The increased incidence of CRC in IBD patients appears to be most pronounced in individuals with extensive and long-term ulcerative colitis.2 The rate of CRC begins to increase significantly after 10 years of colitis, with a cumulative probability of 18% after 30-year duration. Like its more common counterpart, sporadic CRC, the prognosis for IBD-associated CRC is poor: the 5-year survival rate is about 50%. Preventative treatment includes colectomy and the use of drugs. Retrospective studies suggest that chronic treatment with 5-aminosalicylic acid or related drugs can reduce the incidence of CRC in patients with IBD, although the studies are not conclusive, and the mechanism of drug action is uncertain. COX-2 inhibitors may also provide protection and appear to have less potential to aggravate IBD than other nonsteroidal antiinflammatory drugs. Despite potential preventative measures in these patients, the incidence of CRC remains high, and new therapeutic modalities must be explored. Moreover, improved animal models are needed to better understand the disease, to test new treatments, and to understand the mechanisms of action of various treatments. In this regard, several rodent models have been developed to study the pathogenesis of chronic ulcerative colitis and...

Vanilloid Receptor-1 Regulates Neurogenic Inflammation in Colon and Protects Mice from Colon Cancer

“…Moreover, induction of a mild colitis in mice deficient in PACAP has been shown to trigger rapid development of colorectal tumors without the use of a carcinogen. Absence of PACAP led to increased tumor incidence and severity as a consequence of the enhanced inflammatory response to DSS (19). As in the TRPV-1 À/À mice subjected to CAC challenge, clinical symptoms, inflammatory changes, and proinflammatory cytokine responses were significantly more severe in PACAP knockout versus WT controls.…”

“…Among them, substance P and calcitonin gene-related peptide (CGRP) are the best characterized, and because of its proinflammatory nature, they are thought to play a significant role in the development and pathogenesis of colitis (6). In contrast, other neuropeptides such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are endowed with anti-inflammatory properties and they have been suggested to protect colon from inflammation (17)(18)(19). Thus, activation of enteric sensory neurons might lead to the secretion of both pro-and anti-inflammatory neuropeptides, being the balance between both types of neuropeptides what determines the degree of inflammation and in last term, tumor development.…”

DcR3 Protects Islet β Cells from Apoptosis through ModulatingAdcyap1andBank1Expression

“…It has profound effects in various tissues and organs. It is involved in circadian rhythm (29,30), cerebellum development (31,32), energy homeostasis and regulation of body weight (33,34), embryo implantation (35), inhibition of inflammation (36), promotion of regulatory T cell generation (37), and maintenance of pulmonary vascular tone (38), to name a few of its functions. The following Adcyap1 functions are probably directly related to the findings in this study: 1) Adycap1 is antiapoptotic for neurons experiencing ischemia (39); 2) it is present in the nerve fibers innervating the islets (40), and it is produced by ␤ cells (28); 3) adcyap1 can stimulate insulin release (40) by ␤ cells; and 4) tg Adcyap1 overexpression in islet ␤ cells protects ␤ cells from STZ-induced apoptosis and renders the Tg mice resistant to STZ-induced diabetes (41).…”

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

“…Conversely, levels of anti-infl ammatory cytokines such as IL-10 were only one third of that of wild type mice in the distal colon. Using a longer exposure to DSS (2 months), Nemetz and coworkers [ 96 ] described similar results. After induction of colitis by exposure to DSS, PACAP knockout animals displayed more severe clinical symptoms and higher histological infl ammation scores (50-70 % higher), restricted to the distal colon.…”

“…In addition, induction of IL-1beta and IL-6 mRNA expression levels were signifi cantly higher (70 %) in PACAP-defi cient mice. Interestingly, 60 % of PACAP KO mice developed colorectal tumors with aggressive-appearing pathology [ 96 ]. As both studies showed, PACAP-defi cient mice receiving normal water without DSS displayed no signs of infl ammation (and of colitis), suggesting that the lack of endogenous PACAP does not result in immune depression leading to spontaneous development of colitis.…”