[Rectal and colonic polyps and polyposis as precancerous diseases].
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Adenoma↗
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[New molecular biology pathomechanisms for development of hereditary, non-polyposis associated colorectal cancer].
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Cell Transformation, Neoplastic↗
[Recent notions on intestinal cancerogenesis, their implications in genetic risk screening and preventive action of non-steroid anti-inflammatory agents].
Colorectal cancer is the most common malignant tumor in the french population. This tumor represents 45% of the cancers of the digestive tract in female and 60% in male. It is one of the main problem in the field of Public Health but recent progress for research, prophylaxis and treatment have been performed. There are two different pathogenic pathways for colorectal cancer. In chromosomal instability a sequence of rearrangements leads step by step from normal to adenoma and to carcinoma. It is the common pathway observed in 85% of colorectal cancers, mainly localized in left colon. In genic nucleotidic instability loss of tumor-suppresor genes and activation of cellular oncogenes are the consequence of DNA mismatch repair system, which is controlled by several genes. The defect of DNA mismatch repair leads to a hypermutable state in which simple repetitive DNA sequences are specially instable. This is the basis for a test to demonstrate nucleotidic instability. This pathway is found in the remaining 15% of colorectal cancers which are mainly localized on right colon. A mutational inactivation of both alleles of APC gene is considered as an initial gatekeeper event although some cancers begin with a mutation in beta-catenin gene which has the same functional impact. APC expression plays central role in regulating the rate of beta-catenin degradation. Destruction of beta-catenin prevents its translocation into the nucleus where it promotes cellular proliferation. About 5% of colorectal cancer are developed in a high risk population, Familial Adenomatous Polyposis coli (FAP) or Hereditary Non Polyposis Colon Cancer (HNPCC). FAP is caused by a germline mutation in APC gene. Every cell harbors a mutation of an APC allele which insures that a large number of adenomas will occur once an inactivating event occurs on the other wild-type APC allele. The demonstration of a constitutional mutation in a family allows to limit the survey only to the carriers. The phenotypic expression (attenuated, profuse, associated with extra-intestinal lesions) is correlated with the site of the APC mutation. Thus the determination of this site occurs in the choice of the treatment. HNPCC is suggested on clinical and genealogical criterions (young age of onset of cancer, multiple family members affected with cancer in multiple generations, the association of certain tumors in an individual of family, multiple tumors). A biological test may be useful to demonstrate the nucleotidic instability (MSI: microsatellite instability). Constitutional mutations on the mismatch repair genes, mainly MSH2 and MLH1, cause HNPCC syndrome. Endometrial and urethelial malignant tumors are frequent in an individual or in the family. The proven or suspected carriers of mutations undergo colonoscopic surveillance every 1 to 2 years, starting at age 25. An anti-tumoral action of the non steroidal antiinflammatory drugs (NSAID) is now recognized. Firstly observed in animal models of colon cancer the suppressive action was demonstrated in patient with Familial Adenomatous Polyposis. From the results of several epidemiological studies the suppressive action can be generalized to common intestinal tumors. This effect is in relation with the cyclooxygenase 2 inhibition. Other independent pathways intervene: NSAID interfere with beta-catenin, decreasing its action on cellular division. The indication of NSAID and more specifically of COX2 inhibitors in the prophylaxis of colo rectal cancer are yet questioned. The results of trials in progress are expected.
Anti-Inflammatory Agents, Non-Steroidal↗
Adenomatous polyposis coli-deficient zebrafish are susceptible to digestive tract neoplasia.
Truncation of the tumour suppressor adenomatous polyposis coli (APC) constitutively activates the Wnt/beta-catenin signalling pathway. This event constitutes the primary transforming event in sporadic colorectal cancer in humans. Moreover, humans or mice carrying germline truncating mutations in APC develop large numbers of intestinal adenomas. Here, we report that zebrafish that are heterozygous for a truncating APC mutation spontaneously develop intestinal, hepatic and pancreatic neoplasias that are highly proliferative, accumulate beta-catenin and express Wnt target genes. Treatment with the chemical carcinogen 7,12-dimethylbenz[a]anthracene accelerates the induction of these lesions. These observations establish apc-mutant zebrafish as a bona fide model for the study of digestive tract cancer.
Adenoma↗
AOM-induced mouse colon tumors do not express full-length APC protein.
While evidence in both sporadic and inherited human colorectal cancer and MIN mice implicate the tumor suppressor gene, APC, in the causation of colorectal carcinogenesis, this gene has not been confirmed to be involved in rodent chemically-induced colon cancer models (RCCM). These experimental models are widely used to elucidate mechanisms involved in colon carcinogenesis (initiation, promotion and progression) as well as studies on chemoprevention (dietary and other) and intervention. To validate the RCCM as relevant models for sporadic human colorectal cancer, and to facilitate research on the role of the APC gene in colon carcinogenesis, we investigated the role of APC in azoxymethane (AOM)-induced colorectal tumors in mice. Using an antibody that recognizes the carboxy terminus of APC, we have characterized the pattern of staining observed in normal mouse intestinal tissue, in MIN mouse intestinal adenomas and in AOM-induced mouse colon tumors. The APC protein was localized in the cytoplasm of normal colonic epithelial cells. In the small intestine there was APC immunoreactivity along the villous and staining of the Paneth cells at the base of the glands. In the proximal and distal colonic crypts there appeared to be a gradient of staining which increased towards the luminal surface. This gradient was not as apparent in the small intestinal villi. Nuclei and mucus in the goblet cells showed no immunoreactivity. MIN mouse small bowel and colonic adenomas, known to have lost APC, stained negatively for APC. AOM-induced adenomas and carcinomas also consistently stained negatively using this antibody. This study demonstrates for the first time the loss of wild-type APC protein in AOM-induced mouse colon tumors and suggests that alterations in expression of this tumor suppressor gene, which is so commonly mutated in human colon cancer, is also involved in this animal model of colon cancer.
Adenoma↗
Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis.
Although nonsteroidal antiinflammatory drugs (NSAIDs) show great promise as therapies for colon cancer, a dispute remains regarding their mechanism of action. NSAIDs are known to inhibit cyclooxygenase (COX) enzymes, which convert arachidonic acid (AA) to prostaglandins (PGs). Therefore, NSAIDs may suppress tumorigenesis by inhibiting PG synthesis. However, various experimental studies have suggested the possibility of PG-independent mechanisms. Notably, disruption of the mouse group IIA secretory phospholipase A(2) locus (Pla2g2a), a potential source of AA for COX-2, increases tumor number despite the fact that the mutation has been predicted to decrease PG production. Some authors have attempted to reconcile the results by suggesting that the level of the precursor (AA), not the products (PGs), is the critical factor. To clarify the role of AA in tumorigenesis, we have examined the effect of deleting the group IV cytosolic phospholipase A(2) (cPLA(2)) locus (Pla2g4). We report that Apc(Min/+), cPLA(2)(-/-) mice show an 83% reduction in tumor number in the small intestine compared with littermates with genotypes Apc(Min/+), cPLA(2)(+/-) and Apc(Min/+), cPLA(2)(+/+). This tumor phenotype parallels that of COX-2 knockout mice, suggesting that cPLA(2) is the predominant source of AA for COX-2 in the intestine. The protective effect of cPLA(2) deletion is thus most likely attributed to a decrease in the AA supply to COX-2 and a resultant decrease in PG synthesis. The tumorigenic effect of sPLA(2) mutations is likely to be through a completely different pathway.
Adenomatous Polyposis Coli Protein↗
Desmoid tumors in patients with familial adenomatous polyposis.
BACKGROUND: Sporadic desmoid tumors occur mainly in the abdominal wall and in extraabdominal sites. Desmoid tumors in patients with familial adenomatous polyposis (FAP) usually occur in the abdominal wall and in the bowel mesentery. Surgical resection of desmoids in patients with FAP has been controversial. METHODS: A retrospective review of patients with FAP and desmoid tumors treated from 1950 to 1991 was performed. Patients were evaluated for gender, age, site of desmoid tumors, treatment, recurrence, and survival. RESULTS: Twenty-one of 24 patients underwent 60 surgical procedures related to the desmoid tumors. Seven of nine patients who underwent potentially curative surgery had recurrences; three were reresected. Major morbidity after palliative or curative surgery was 47%. Five patients were alive with no evidence of disease at a median of 198 months, 10 patients were alive with disease at a median of 102 months, and 5 patients died with disease at a median of 31 months after diagnosis. CONCLUSIONS: Desmoid tumors are common in patients with FAP. Unresectability and recurrence are more common than cure. Palliative and curative resections have a high morbidity. Surgery should be reserved for those patients with symptomatic mesenteric desmoids.
Abdominal Neoplasms↗
Molecular dimensions of gastrointestinal tumors: some thoughts for digestion.
Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
Colonic Polyps↗
Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation.
Affected members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at an early age (mean 45 yr) and frequently get extracolonic cancers particularly in the uterus, urinary tract, and small intestine. They have a high risk of developing more than one primary colorectal cancer if not treated with subtotal colectomy at first operation and have more frequent right-sided colon cancers and less frequent rectum cancers, compared to patients with sporadic colorectal cancer. We have screened 31 families fulfilling the Amsterdam criteria and 54 families with a colorectal cancer clustering but not fulfilling the Amsterdam criteria for mutations in MLH1 and MSH2 by direct sequencing, and detected a mutation in 61% of the Amsterdam positive families but only in 15% of the Amsterdam negative families. Genotype-phenotype correlation was compared between 141 affected individuals with an identified mutation and 78 affected individuals from Amsterdam positive families in which a mutation was not identifiable in MLH1 or MSH2. In the affected persons with identified mutations, all expected phenotypic traits were represented, whereas affected persons in whom no mutation was detected fell into two clearly distinguishable subgroups. The minor subgroup, in which no mutation was identified, generally had the same characteristics as found in affected persons with identified mutations. The major subgroup differed significantly in clinical features and exhibited phenotypic traits similar to those found in late-onset families, including abundance of rectal cancer, few HNPCC-related cancers, lower frequency of multiple colorectal cancers, and later age at onset. Finally, for six missense mutations and one single codon deletion, the pathogenic potential was evaluated by domain localization, lod score calculation or segregation analysis when possible, and mutation-induced biochemical change. The results indicate that the majority of missense mutations are pathogenic, although further characterization by functional assays is necessary before implementation in predictive testing programs.
Adaptor Proteins, Signal Transducing↗
Effects of short chain fatty acids on mucosal proliferation and inflammation of ileal pouches in patients with ulcerative colitis and familial polyposis.
PURPOSE: To verify whether short chain fatty acids (SCFA) alter the proliferative and endoscopic pattern of the mucosa in ileal pouches of ulcerative colitis (UC) or familial adenomatous polyposis (FAP) patients. METHODS: We studied patients after proctocolectomy carrying a pelvic ileal pouch for FAP or UC (noncanalized pouches in 10 UC and 4 FAP patients and canalized pouches in 6 UC and 5 FAP patients). Patients with noncanalized pouches were treated twice daily for one week with 30 ml of a SCFA solution (60 mM sodium acetate, 30 mM sodium propionate, 40 mM sodium butyrate, and 22 mM sodium chloride, pH 7); patients with canalized pouches were treated with the same solution twice daily for two weeks. Pouch mucosal biopsies were collected before and after SCFA. Mucosal proliferation was assessed by incorporation of [3H]thymidine in vitro and autoradiography. RESULTS: In UC patients proliferation did not vary in noncanalized pouches but was significantly reduced in canalized pouches after SCFA. In FAP patients SCFA did not alter proliferation. No significant effects of SCFA were observed on daily defecation frequency, endoscopic appearance, or histopathology of the pouches. CONCLUSIONS: SCFA do not control inflammation and clinical functions but reduce cell proliferation in UC patients. On the contrary, FAP patients are refractory to SCFA.
Adenomatous Polyposis Coli↗
Pattern of mucosal adaptation in acute and chronic pouchitis.
PURPOSE: Variant pathological changes have been observed in ileoanal pouches, including inflammation, villous atrophy, and crypt hyperplasia. Therefore, we investigated the type and degree of mucosal adaptation in patients with ulcerative colitis and familial adenomatous polyposis. METHODS: Forty-two patients with ulcerative colitis and 14 patients with familial adenomatous polyposis with ileoanal pouches were assessed. Samples were taken from three months to eight years after creation of an ileoanal pouch. Mucosal architecture was examined by morphometry after microdissection. RESULTS: Structural changes of the mucosa can be categorized into three groups. Compared with preoperative values, patients without pouchitis (73 percent) has only minor decrease of villous length (402 microm vs. 540 microm) and increase in crypt depth (274.5 microm vs. 177 microm). In patients with acute pouchitis (20 percent), a slight increase in villous length (477 microm vs. 402 microm) and pronounced crypt hyperplasia (376 microm vs. 274.5 microm) was observed compared with noninflamed ileoanal pouches. In contrast, in patients with chronic pouchitis (7 percent), severe villous atrophy (62.5 microm) and crypt hyperplasia (543 microm) was found. CONCLUSIONS: Minor structural changes of ileoanal pouch mucosa develop early as an adaptive response to a new environment. Only in a small group of patients with chronic pouchitis does severe villous atrophy and crypt hyperplasia of the ileoanal pouch mucosa develop, most likely as a consequence of mucosal inflammation.
Adenomatous Polyposis Coli↗
Restorative proctocolectomy: morphological and functional study with coronal CT.
BACKGROUND: Restorative proctocolectomy with ileal pouch has become the surgical treatment of choice for patients with ulcerative colitis (UC) and familial polyposis of the colon. Defecography is the radiological technique commonly employed to obtain detailed information on function and morphology of the ileal pouch; it allows the direct visualization of the ileal pouch and the anal canal, but it does not provide the visualization of the pelvis. METHODS: In all patients, computed tomography (CT) on coronal planes was performed to determine its possibilities as an alternative to defecography; 10 patients with UC submitted to restorative proctocolectomy and were examined. RESULTS: Coronal CT images provided a panoramic vision of the pelvis and demonstrated the morphology of the ileal pouch, the thickness of its walls, and its correlation with the surrounding tissues. Coronal CT also allowed the evaluation of the continence of ileo-anal and ileo-ileal anastomosis and the functional changes of the perineal muscles at rest and during squeezing. CONCLUSION: CT images acquired on coronal planes allows an easy and clear detection of the major postoperative complications, such as stenosis or dehiscences of the anastomosis, pelvic phlogosis, and fistulae.
Adenomatous Polyposis Coli↗
Increased level of mitochondrial gene expression in polyps of familial polyposis coli patients.
To elucidate the mechanism of polyp formation in familial polyposis coli patients, cDNA clones, expressed differently between normal colonic mucosae and polyps, were screened. Three polyp-derived cDNA clones showed increased levels of transcription under neoplastic conditions. Among them, clone P6 was determined to be derived from the mtDNA encoding parts of subunit 1 of NADH dehydrogenase and 16S rRNA. The number of copies and restriction enzyme patterns of the mtDNA did not vary in either normal or neoplastic tissues, and a level of different mitochondrial mRNA was increased in the same proportion, suggesting a change in the rate of synthesis and/or degradation of the mtRNA. No cDNA clone which was expressed higher in normal colonic mucosae than in polyps was isolated from the cDNA library derived from normal mucosae.
Adenomatous Polyposis Coli↗
Loss of extracellular E-cadherin in the normal mucosa of duodenum and colon of patients with familial adenomatous polyposis.
The duodenum is the main site for (pre-) malignant extracolonic manifestations in patients with familial adenomatous polyposis (FAP). Changes in the E-cadherin/beta-catenin complex play a pivotal role in the development of malignancies. Loss of E-cadherin has been described in association with loss of SMAD4. To elucidate the pathways leading to the development of duodenal adenomas in patients with FAP, the distributions of E-cadherin, SMAD4, and beta-catenin were analyzed. Furthermore, differences between the duodenum and colon were evaluated. Normal FAP duodenum (n = 13) and FAP duodenal adenomas (n = 50; total, 21 patients) were compared with non-FAP duodenal adenomas (n = 7) and normal non-FAP duodenum (n = 15) by immunohistochemical staining for extracellular and intracellular E-cadherin, beta-catenin, and SMAD4. Colonic biopsies of 10 patients with FAP were also studied, as well as non-FAP colonic adenomas (n = 26) and non-FAP normal colon (n = 12). Compared with the intracellular component of E-cadherin that was present in all cases, a significant loss of extracellular E-cadherin was observed in both duodenal and colonic adenomas and normal tissue of patients with FAP. Nuclear localization of beta-catenin was more often observed in duodenal FAP adenomas compared with non-FAP adenomas. Loss of nuclear SMAD4 was seen in the duodenum and, to a higher degree, in the colon of patients with FAP, as well as non-FAP patients. The loss of extracellular E-cadherin in the normal duodenal and colonic mucosa of patients with FAP might play a role in the high susceptibility of these tissues for (pre-) malignant transformation.
Adenoma↗
Gastrointestinal polyposis syndromes.
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Adenomatous Polyposis Coli↗
Requirement for tumor suppressor Apc in the morphogenesis of anterior and ventral mouse embryo.
Tumor suppressor Apc (adenomatous polyposis coli) is implicated in the Wnt signaling pathway that is involved in the early embryonic development and tumorigenesis in vertebrates. While the heterozygous null mutant mice develop intestinal polyps, the homozygous embryos die before gastrulation. To investigate the role of Apc in later embryonic development, we constructed a novel hypomorphic Apc allele whose expression was attenuated by approximately 80%. In the hypomorphic Apc homozygous ES cells, reduction in Apc expression caused beta-catenin accumulation and Wnt signaling activation. The homozygous mutant mouse embryos survived 3 days longer than the null mutant embryos. Interestingly, they showed anterior truncation, partial axis duplication, and defective ventral morphogenesis. To determine the tissues where Apc functions for anterior and ventral morphogenesis, we constructed chimeric embryos whose epiblast was derived predominantly from the Apc hypomorphic homozygous cells but the visceral endoderm was from the wild type. Although these chimeric embryos still showed some anterior defects, their ventral morphogenesis was rescued. In addition, marker studies indicated that the axial mesendoderm was also defective in the homozygous embryos. Our results provide genetic evidence that expression of Apc at the normal level is essential for both anterior and ventral development, in the epiblast derivatives and visceral endoderm.
Alleles↗
Familial adenomatous polyposis.
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Adenomatous Polyposis Coli↗
Use of novel immunohistochemical markers expressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma.
Distinguishing primary ovarian carcinoma, particularly endometrioid and mucinous subtypes, from metastatic colorectal carcinoma to the ovary is often difficult on histologic examination alone. Recently, three immunohistochemical markers CDX2, a homeobox gene encoding an intestine-specific transcription factor; alpha-methylacyl-CoA racemase (AMACR/P504S), a mitochondrial and peroxisomal enzyme with fairly restricted expression in selective tumors and beta-catenin, an adenomatous polyposis coli (APC) mutation product resulting in activation of the Wnt pathway, have been reported to have specific and sensitive expression in colorectal carcinomas. We evaluated a panel consisting of antibodies to CDX2, beta-catenin and P504S in 23 primary ovarian adenocarcinomas (13 mucinous and 10 endometrioid) and compared the findings to 22 metastatic colorectal adenocarcinomas (seven mucinous and 15 nonmucinous tumors with endometrioid-like morphology hereafter referred to as pseudo-endometrioid) to the ovary stained with the same panel. Twenty (91%) metastatic tumors expressed at least two markers and seven (32%) expressed all three. In contrast, only three (13%) primary ovarian tumors expressed at least two markers and none expressed all three. Strong (2+, 3+) and diffuse (>40%) expression for CDX2 was noted in 21 (95%) metastatic tumors and five (22%) primary ovarian tumors (three mucinous, two endometrioid). P504S was similarly expressed in seven (32%) metastatic and none of the primary ovarian carcinomas. Nuclear expression of beta-catenin was noted in 13 (59%) metastatic tumors and in eight cases (36%), it was diffuse and strong. In contrast, four (19%) primary tumors showed nuclear expression of this protein with only one (5%) case expressing it in a diffuse pattern. Immunohistochemical expression of gene products and enzymes of colorectal carcinogenesis in some primary ovarian carcinomas suggest that the morphologic similarities between colorectal and mucinous/endometrioid carcinoma of the ovary extends to the genetic level, although differences in the level of expression exist between these tumors. Diffuse expression of all three markers (CDX2, beta-catenin and P504S) in a tumor in the ovary was found to be virtually diagnostic of metastasis from a colorectal primary in this study.
Adenocarcinoma↗