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THEMES
Gastrointestinal Division, Mount Sinai School of Medicine, New York, New York 10029
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ABSTRACT |
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 TOP ABSTRACT CLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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B and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.
inflammatory bowel disease; colorectal cancer; colitis; oxidative stress; animal models
Regardless of the underlying condition, essentially all CRCs develop from a dysplastic precursor lesion. In sporadic CRC, the dysplastic precursor is the adenomatous polyp (adenoma), a discrete focus of neoplasia that is typically removed by simple endoscopic polypectomy. In contrast, dysplasia in patients with IBD can be polypoid or flat, localized, diffuse, or multifocal and, once found, marks the entire colon as being at heightened risk of neoplasia, thereby warranting surgical removal of the entire colon and rectum. These differences in morphology and biological behavior not only make clinical cancer surveillance in IBD patients more challenging than in the general population, but they raise the important question of how chronic inflammation contributes to the development of CRC. The "adenoma-carcinoma" sequence found in the sporadic setting becomes the "inflammation-dysplasia-carcinoma" sequence in IBD. The object of this theme article is to first review the clinical and molecular features of CRC in IBD and then discuss how inflammation may contribute to CRC pathogenesis.
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CLINICAL FEATURES OF COLITIS-ASSOCIATED CRC |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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Several lines of evidence implicate chronic inflammation as a key predisposing factor to CRC in IBD (46). First, the risk for developing CRC increases with longer duration of colitis. Although, for some reason, CRC is rarely encountered before seven years of colitis; thereafter, the risk increases at a rate of 
0.5–1.0% per year. Second, the extent of colitis is another important risk factor; the more colonic surface that is involved with colitis, the greater the colon cancer risk. Paradoxically, however, patients who have inflammation limited only to the rectum do not have an appreciably increased risk of cancer. Third, the risk of CRC is much greater in the small subset of IBD patients who also have primary sclerosing cholangitis, an idiopathic condition characterized by chronic inflammation of the bile ducts, which predisposes not only to CRC but also to biliary tract cancer. Fourth, evidence is mounting to suggest that anti-inflammatory medications, especially 5-aminosalicylates but possibly corticosteroids, can reduce the development of colorectal dysplasia and cancer in IBD. This situation is similar to healthy individuals and even those with FAP, in whom the use of aspirin or other nonsteroidal anti-inflammatory agents has been shown to diminish the growth and subsequent development of colorectal neoplasia.
Despite all of the evidence strongly implicating chronic inflammation as the culprit, surprisingly little research has directly addressed the question of whether inflammation per se correlates with CRC risk in IBD. In fact, historically, the degree of colitis activity has been considered not to be an independent risk factor for CRC, probably because of the way that disease activity was defined. For example, when activity of disease was measured according to the frequency of clinical (symptomatic) exacerbations, there did not appear to be a correlation with CRC risk (25, 64). However, when colitis activity has been defined histologically, a recent case-control study found that greater degrees of histologically active inflammation were indeed associated with increased risk of CRC (74). New evidence also indicates that CRC can arise in areas of microscopic colitis proximal to areas of gross colitis, suggesting that histological change, even without colonoscopic alteration, is a better determinant of inflammation for the purposes of cancer risk (54). It is important to realize though, that patients with the most severe inflammation often undergo colectomy early in their disease because they are not responding to medical therapy. As such, they are no longer at risk for developing CRC. Ironically then, many patients who develop CRC in IBD have clinically, as well as histologically, quiescent inflammation. Active inflammation in colorectal mucosa is characterized by a predominant neutrophilic infiltration with crypt abscesses and ulceration of the epithelium. Inactive, or quiescent, inflammation is marked by a predominance of lymphocytes. Thus better insight into the pathogenesis of CAC will likely come from studying the role of the immune cells and their products. This will be reviewed below, following a brief overview of the molecular pathogenesis of CAC.
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MOLECULAR PATHOGENESIS OF SPORADIC CRC |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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Loss of APC function is typically an early event in SCC pathogenesis, giving the APC gene the monicker of "gatekeeper" of the colon (Fig. 1). Although some have argued that APC mutation may not be the universal initiating event but may instead occur at somewhat later stages of adenoma progression (48), APC still contributes to the process of CIN (32). During the progression of the adenoma, whereby increases in adenoma size, degree of dysplasia, and degree of villous histology take place, other changes in genetic regulation occur, such as induction of the k-ras oncogene and loss of function of tumor suppressor genes on chromosome 18q in the region of the deleted in colon cancer (DCC) and deleted in pancreatic cancer (DPC4) genes. Loss of p53 gene function occurs late and is believed to be the defining event that drives the adenoma to carcinoma.
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RII, IGF2R, and BAX, which contain in their coding regions short nucleotide repeats that are intrinsically unstable and therefore prone to be copied incorrectly during DNA replication. The resulting microsatellite instability renders these genes incapable of normal colonocyte homeostasis resulting in malignant growth. This pathway of colon carcinogenesis has been referred to as the "mutator" pathway because of the many mutations in key genes involved. Compared with MSS sporadic colon cancers, MSI sporadic colon cancers are more likely to be diploid (normal DNA content), located in the proximal colon, mucinous, poorly differentiated, show lymphocytic infiltration, and associated with a more favorable prognosis (48). MSI-positive CRCs can be further classified into those with high (MSI-H) or low (MSI-L) degrees of MSI depending on how many markers of a consensus panel are found to be unstable (8). Epigenetic alterations also contribute to altered gene expression in colon carcinogenesis. A recently recognized molecular alteration is the CpG island methylator phenotype (CIMP) (85). CpG islands are dense aggregates of cytosine-guanine dinucleotide sequences that may occur in the promoter region of genes. Extensive methylation of the cytosine bases is associated with promoter silencing and loss of gene expression. Many genes involved in cell cycle control, cell adhesion, and DNA repair can be methylated in colon cancer (75). So-called type A methylation, i.e., the estrogen receptor, occurs as a function of age and is found in both normal colon and colon cancer. Type C methylation, however, is cancer associated, leading to pathogenic silencing of genes such as hMLH1, MGMT, p16, and p14.
In general, tumors manifest either the CIN or the MSI phenotype. However, there can be overlap between the CIMP and MSI phenotype. For example, hypermethylation of hMLH1 can produce the MSI-H cancer phenotype. By the same token, methylation of MGMT rather than hMLH1 underlies MSI-L cancers (48). The process of methylation is an area of intense investigation, and it is anticipated that this line of research will help to better define the molecular pathways involved in CRC in a variety of clinical settings including IBD.
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MOLECULAR PATHOGENESIS OF COLITIS-ASSOCIATED CRC |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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Perhaps not surprisingly, many of the molecular alterations responsible for SCC development also play a role in colitis-associated colon carcinogenesis. In fact, emerging evidence suggests that in CAC, the frequency of CIN (85%) and MSI (15%) is roughly the same as in SCC (87). Distinguishing features of CAC, however, are differences in the timing and frequency of these alterations (Fig. 1). For example, APC loss of function, considered to be a very common early event in SCC, is much less frequent and usually occurs late in the colitis-associated dysplasia-carcinoma sequence (4, 68, 84). Mutations in APC are rarely, if ever, encountered in colitic mucosa that is negative or indefinite for dysplasia, and fewer than 14% of tissues manifesting LGD or cancer harbor APC mutations (4, 68, 86). Likewise, allelic deletion of APC occurs in fewer than 33% of colitis-associated neoplasms (86).
Greater evidence implicates p53 as playing an instrumental role in CAC. Allelic deletion of p53 occurs in 50–85% of cancers (13, 89). Indeed, p53 LOH correlates with malignant progression, occurring in 6% of biopsies without dysplasia, 9% with indefinite dysplasia, 33% with LGD, 63% with HGD, and 85% with cancer (13). In the setting of colitis, p53 mutations occur early and are often detected in mucosa that is nondysplastic or only indefinite for dysplasia (10, 13). In carefully mapped colectomy specimens, p53 mutation was an early molecular change that occurred before aneuploidy, which, in turn, preceded p53 LOH (Fig. 1) (10). In fact, a high frequency of p53 mutations was found in inflamed mucosa from UC patients who did not have cancer, indicating that chronic inflammation predisposes to these early mutations (see below) (43).
Methylation is assuming increasing importance as a mechanism contributing to the genetic alterations in CAC (Fig. 1). Indeed, methylation of CpG islands in several genes seems to precede dysplasia and is more widespread throughout the mucosa of UC patients (45). In colitis-associated neoplasms, hMLH1 hypermethylation was observed in 6 of 13 (46%) MSI-H, 1 of 6 (16%) MSI-L, and 4 of 27 (15%) MSS specimens, implicating this epigenetic change as a cause of microsatellite instability (31). The cell cycle inhibitor p16INK4a, the loss of which has been implicated in sporadic CRC, is commonly hypermethylated in UC neoplasms (42). Approximately 10% of biopsies without dysplasia already demonstrate p16 promoter hypermethylation, the rate increasing with higher grades of dysplasia and reaching 100% in cancer specimens. p14ARF is an indirect regulator of p53, and it resides at the same locus as p16INK4
. Loss of p14ARF function by promoter hypermethylation has been reported in 50% of adenocarcinomas, 33% of dysplastic lesions, and even in 60% of mucosal samples without dysplasia from patients with UC (76).
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THE ROLE OF CHRONIC INFLAMMATION IN COLON CARCINOGENESIS |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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For one thing, the colonic mucosa of patients with IBD demonstrates enhanced epithelial cell turnover. Compared with normal colonic biopsies taken from patients with sporadic adenomas, mucosal biopsies from patients with UC demonstrate higher rates of mitosis as well as apoptosis, especially in areas of active, as opposed to quiescent, inflammation (3). However, whereas increased epithelial cell turnover likely contributes to carcinogenesis, it is insufficient to cause cancer. Rather, in the setting of heightened epithelial cell turnover, mutagenic assault and sustained DNA damage caused by factors within an inflammatory cell-rich microenvironment appear to drive the carcinogenic process. As such, tumors behave similar to wounds that fail to heal (20).
A leading theory is that the oxidative stress that accompanies chronic inflammation contributes to neoplastic transformation. Indeed, IBD is considered one of the main "oxyradical overload" diseases whereby chronic inflammation, be it inherited or acquired, results in a cancer-prone phenotype (44). Oxidative stress, with its associated cellular damage, is thought to play a key role in the pathogenesis of the colitis itself as well as in colon carcinogenesis (Fig. 2). Colitis is triggered in a genetically susceptible individual by an environmental insult such as gastrointestinal infection, NSAID use, or other environmental toxins. The inflammatory cells that contribute to the colitis generate reactive oxygen and nitrogen species (RONS). Neutrophils and macrophages, which are important in the acute inflammatory process, generate free radicals and other prooxidant molecules. Inflamed tissues from patients with active UC or Crohn's colitis demonstrate increased expression of NOS and other RONS (40, 43, 50, 66). With the use of GAPDH enzyme as a molecular marker, McKenzie et al. (55) showed that oxidation of thiols in the active site of GAPDH, with subsequent inhibition of enzyme activity, occurred in colonic epithelial cells from inflamed mucosa of Crohn's disease and UC but not from paired samples of unaffected mucosa. Measurements of 8-hydroxydeoxyguanosine (8-OHdG), a mutagen formed by the action of hydroxyl radical at the C8 position of deoxyguanosine DNA base, in mucosal biopsies of patients with UC were reported to be increased in patients with UC compared with normal controls, with levels even higher in UC patients who had dysplasia (23). Interestingly, 8-OHdG levels were increased with longer duration of UC and were lowest in the rectum, suggesting that the meselamine enemas that most of these patients were using might have had an antioxidant effect.
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How then might oxidative stress contribute to colorectal carcinogenesis? Free radicals have the potential to affect a large array of metabolic processes, because their targets include DNA, RNA, proteins, and lipids (44, 53). If key genes or proteins responsible for colonocyte homeostasis are targeted, dysplasia and subsequent carcinoma arise. The p53 tumor suppressor gene is one important target. Hussain et al. (43) examined the mutation spectrum of p53 at codons 247 and 248 in biopsies taken from inflamed colonic mucosa of UC patients compared with normal, non-UC controls. They noted that more than half of the UC cases exhibited a higher frequency of G-to-A transitions at the CpG site of codon 248 and C-to-T transitions at the third base of codon 247 compared with controls. Moreover, in paired biopsies from UC patients, this pattern of mutation was only seen in inflamed rather than noninflamed mucosa. Increased NOS-2 activity was associated with these p53 mutations, suggesting that oxidative stress was playing a role. These investigators also observed that increases in posttranslational modifications of p53 were associated with increased iNOS activity in inflamed tissues from UC patients, further implicating activated p53 in response to oxidant injury (40).
More direct evidence for the role of RONS in colon carcinogenesis comes from the work of Gasche et al. (33), who used model colon cancer cell lines to observe that hydrogen peroxide (H2O2) produced frameshift mutations in a reporter gene. In their system, cells that were genetically deficient in DNA MMR activity were particularly susceptible to frameshift mutations, but even at higher concentrations of H2O2, cells with normal MMR activity displayed frameshift mutations. In subsequent studies, these investigators found that H2O2 inactivated the DNA MMR system, apparently by damaging the protein complexes responsible for DNA base mismatch repair (15). Conceivably therefore, even in the absence of mutations of the relevant genes, oxidative stress may put enough "pressure" on the DNA MMR system to create microsatellite instability, and this presumably contributes to the MSI phenotype seen both in nonneoplastic and in neoplastic mucosa of UC patients. A recent discovery suggests that increased activity of enzymes responsible for the process of base excision-repair might also contribute to MSI in UC tissues (39). MSI can be detected in chronically inflamed mucosa from UC patients, even in those with rather short disease duration before the risk of neoplasia ostensibly rises (9). This lends credence to the concept that inflammation alone can cause MSI. Curiously, however, MSI is not found in normal colonic mucosa from healthy controls or from patients with other types of benign inflammatory colitis including Crohn's colitis (9, 59). It is tempting to speculate that certain RONS may cause MSI and that the spectrum of RONS differs in the local tissue microenvironment depending on the inflammatory background of the underlying disease.
As mentioned above, chromosomal instability represents the major pathway by which cancers seem to arise in IBD patients. It is not yet clear whether chronic inflammation contributes to this molecular pathway or whether some other factor(s) predisposes. For example, using fluorescent in situ hybridization with probes specific for chromosomes 8, 11, 17, and 18, Rabinovitch et al. (65) reported that patients with UC who had a neoplasm (HGD or cancer) in the colon (so-called progressors) demonstrated CIN both in the neoplastic lesions themselves as well as in nondysplastic rectal mucosa remote from the neoplastic areas. Although normal mucosa from control subjects without UC did not display CIN, inflamed but nondysplastic mucosa of UC patients who did not harbor a neoplasm in their colon (nonprogressors) also did not exhibit CIN. This observation was reinforced by studies in which DNA fingerprinting demonstrated substantial genomic instability in both the dysplastic as well as nondysplastic mucosa of UC patients harboring a neoplasm (16). These findings suggest that widespread genomic instability occurs in patients with UC who develop colonic neoplasia but not in patients with UC who have not yet developed neoplasia despite comparable disease duration and the presence of inflammation. Thus this type of genomic instability may be a marker of cancer risk in UC perhaps apart from the inflammatory process. It has been observed that a possible mechanism to explain the chromosomal instability associated with UC is telomere shortening (63). Given the importance of the CIN pathway in CAC, it will be important to more directly study the role of inflammation in this process.
Oxidants can also alter DNA methylation patterns (78). It is not yet known whether the hypermethylation of genes involved in CAC (45) are affected by oxidant injury.
In addition to damaging DNA and other macromolecules, oxyradicals can also induce key genes involved in the inflammatory and carcinogenic process. For example, the transcription factor NF-B can stimulate iNOS to generate NO and COX-2 to generate prostanoids that have proinflammatory and carcinogenic effects (88). Activated NF-kB is found in inflamed mucosal biopsies of patients with IBD (71). Among the factors that can regulate NF-kB activity, TNF- induces NF-kB, whereas peroxisome proliferator-activated receptor-
(PPAR) attenuates NF-kB. At the present time, it is not clear whether TNF- itself plays a role in carcinogenesis nor is it known whether inhibiting TNF-, which is so effective in reducing the inflammation of Crohn's disease, can abrogate the carcinogenic process. PPAR ligands have been shown to inhibit intestinal inflammation (83), and impaired expression of PPAR has been described in colonic epithelial cells of patients with UC (24). Treatment of APC deficient mice with PPAR ligands has yielded mixed results, with both increases and decreases in adenoma growth reported (12, 58). The role of PPAR in colitis-associated cancer has not been investigated.
COX-2 activity plays an important role in sporadic carcinogenesis where it has been shown that normal colonic mucosa does not express COX-2, but with the adenoma-carcinoma sequence, this enzyme is induced. Among the many effects of cyclooxygenases, they can activate procarcinogens, indirectly produce free radicals, and promote angiogenesis (81). In animal models, COX-2 inhibition can dramatically reduce the development of colon cancers, just as in humans, use of COX-2 inhibitors and other NSAIDs is protective against colon cancer (34). In UC, COX-2 expression is somewhat enhanced in inflamed mucosa, but it is further induced in dysplastic and cancerous lesions (1). Whether COX-2 inhibition would be chemopreventive against CRC in the setting of UC is not known. Concern has been raised by a study in the IL-10-deficient mouse model of chronic colitis, where COX-2 inhibitors paradoxically enhanced the frequency of colonic dysplasia (see below) (35).
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LESSONS FROM ANIMAL MODELS |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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DSS COLITIS IN HEALTHY RODENTS |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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20, 44, and 36% for the proximal, middle, and distal colon, respectively (19). Animals that developed neoplasia demonstrated more severe degrees of inflammation, especially in the distal colon (19, 61). The histology of dysplastic and cancerous lesions resembles that of IBD neoplasms, but in contrast to the human situation, none of the cancers and only 7% of dysplasias induced by DSS manifested nuclear p53 immunostaining (19). Parenthetically, in the DSS model, treatment with the antioxidant N-acetylcysteine reduced both the inflammation and tumor incidence (77). In general, these observations support the concept that prolonged and repetitive inflammation promotes colon cancer. |
DSS COLITIS IN CANCER-PRONE MICE |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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The APCMin/+ mouse has also been studied in the context of DSS-induced colitis (18). No cancers arose in APCMin/+ mice that did not receive DSS. In contrast, the frequency of cancers among mice receiving only one or two cycles of DSS was 22 and 40%, respectively. Likewise, DSS induced a very high frequency of dysplasia that arose in areas of healed mucosa as well as those of acute and chronic inflammation. Animals with higher inflammation scores had significantly more dysplastic lesions. Thus colitis markedly accelerates the development of neoplasia in APC mutant mice.
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CANCER AND DYSPLASIA IN IBD-PRONE MICE |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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2-Microglobulin Double Knockout Mice
IL-2 is an essential regulatory cytokine of the immune system. Among IL-2-deficient mice, 50% die within 9 wk with splenomegaly, lymphadenopathy, and severe autoimmune hemolytic anemia (37). The rest develop chronic colitis resembling UC and a systemic wasting disease resulting in death within 6 mo. Within the limited lifespan, dysplasia (37) but not cancers (80) has been observed. The IL-2null and 2-Mnull double knockout mouse develops pancolitis similar to IL-2 knockout mice, but these mice have milder overall disease and are able to survive >6 mo. This offers an opportunity to study colon carcinogenesis. With prolonged observation (6–12 mo), 32% of these mice develop adenocarcinoma in the proximal colon. In addition, LGD and HGD are also noted in these animals (80). Molecular characterization of these cancers revealed that all of the cancers harbored APC gene mutations, more than one-half had p53 gene mutations, and most exhibited MSI (80).
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IL-10 KNOCKOUT MICE |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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levels are elevated, there does not appear to be any downregulation or truncation of the TGF- receptor type II (82). Thus the molecular mechanism of these tumors remains elusive. IL-10 treatment was shown to ameliorate the colitis in all animals and decreased the cancer occurrence by half even after the colitis had been established (7). Likewise, in a small study (62), probiotics also reduced the prevalence of colon cancer and mucosal inflammatory activity. On the other hand, pure cultures of Enterococcus faecalis induced both IBD and, after 20 wk, dysplasia and cancer of the rectum in IL-10–/– mice (5). Paradoxically, COX-2 inhibitors have been shown to exacerbate, rather than ameliorate, the severity of colitis and the frequency of dysplasia in IL-10–/– mice (35). The effect of IL-10 in IBD has also been studied in other colitis models (57). In SCID mice, transfer of CD4+CD45RBhi T cells from normal donors into CB-17 SCID mice resulted in severe colitis. IL-10 has been shown to prevent colitis in this setting. Oral administration of Lactococcus lactis-secreting IL-10 reduced DSS-induced colitis. Taken together, it appears that IL-10 plays an inhibitory/regulatory role in these animal models and that lacking IL-10 resulted in colitis. The chronic inflammation further contributed to the formation of adenocarcinoma. |
RAG2-DEFICIENT MICE |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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TGF-1 AND RAG2 DOUBLE KNOCKOUT MICE
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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T CELL RECEPTOR- KNOCKOUT MICE
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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-deficient mice have defective intestinal mucosal immune systems and develop UC-like colitis. When raised under conventional conditions, TCR- and p53 double knockout mice are not only susceptible to chronic inflammation (90%, most limited to ileocecum and cecum) but are also prone to dysplasia (50–70%) and adenocarcinoma (70%) (49). Germ-free conditions prevent both chronic inflammation and neoplasms. |
GLUTATHIONE PEROXIDASE-1/-2 DOUBLE KNOCKOUT MICE |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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40% of animals develop tumors (28% adenocarcinomas) that are often nonpolypoid and primarily located in the distal ileum (17). Higher tumor rates were correlated with higher inflammation scores in the ileum but not the colon, suggesting that inflammation is necessary but not sufficient to cause tumors. Tumor incidence was highest in colonies that were raised in non-SPF conditions. Essentially no tumors developed in germ-free or SPF colonies nor were there any tumors noted in animals that had at least one wild-type Gpx1 or Gpx2 allele. This model is instructive, because these mice have otherwise intact immune systems and mucosal barrier function, and it highlights the importance of the antioxidant system in protecting against inflammation and neoplasia in the setting of bacterial infection. |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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) resulted in loss of endogenous E-cadherin from the cell surface. Because complete disruption of cadherin production results in embryonic lethality in mice, a chimeric mouse model was created that expressed dominant-negative N-cadherin in the small intestine (36). This was generated by introducing genetically manipulated embryonic stem cells from 129/Sv strain (NCAD) into normal B6 blastocytes. The resultant 129/Sv
B6 chimeric mouse intestine contained patches of 129/Sv (NCAD)-derived crypt-villus units and patches of crypt-villus units of B6 background that were easily distinguishable from 129/Sv by their lectin-binding properties. All chimeric mice developed IBD similar to Crohn's disease, presumably because disruption of the epithelial barrier results in inflammation. Inflammation is present only in 129/Sv (NCAD) patches but not in B6 epithelium, and consequently, foci of dysplasia and adenoma were only found in 129/Sv (NCAD) areas. No adenocarcinomas were observed during the 19 mo of the experiment. This model supports the association between inflammation and tumorogenesis. However, the fact that adenomas occurred in both inflamed and noninflamed 129/Sv (NCAD) patches indicates that a noninflammatory-driven process, such as aberrant cell migration, may also play a role. |
Gi2–/– MICE
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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i2 develop profound alterations in thymocyte maturation and function (73). From 13 wk of age onward, these mice develop severely active colitis, especially in the distal colon, and the intensity and extent of colitis progress with age. By 15–36 wk of age, 31% of mice developed cancer that was not polypoid or metastatic. Large pools of mucin were found in some cancers. |
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTCLINICAL FEATURES OF COLITIS...MOLECULAR PATHOGENESIS OF...MOLECULAR PATHOGENESIS OF...THE ROLE OF CHRONIC...LESSONS FROM ANIMAL MODELSDSS COLITIS IN HEALTHY...DSS COLITIS IN CANCER-PRONE...CANCER AND DYSPLASIA IN...IL-10 KNOCKOUT MICERAG2-DEFICIENT MICETGF-{beta}1 AND RAG2 DOUBLE...T CELL RECEPTOR-{beta} KNOCKOUT...GLUTATHIONE PEROXIDASE-1/-2...N-CADHERIN DOMINANT-NEGATIVE...G{alpha}i2-/- MICEFUTURE DIRECTIONSREFERENCES |
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