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PubMed2001

Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.

Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.

Adenocarcinoma↗
PubMed2001

Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis.

Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.

Adenoma↗
PubMed2006

The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis.

Arginine is catabolized by NOS2 and other nitric oxide synthases to form nitric oxide. We evaluated the roles of dietary arginine and Nos2 in Apc-dependent intestinal tumorigenesis in Min mice with and without a functional Nos2 gene. NOS2 protein was expressed only in intestinal tissues of Apc(Min/+) Nos2+/+ mice. NOS3 expression was higher in intestinal tissues of mice lacking Nos2, mainly in the small intestine. When diet was supplemented with arginine (0.2% and 2% in drinking water), lack of Nos2 results in decreased tumorigenesis in both small intestine and colon. In Nos2 knockout mice, supplemental arginine (up to 2%) caused a decrease in small intestinal tumor number and size. The arginine-dependent decrease was associated with an increase in nitrotyrosine formation and apoptosis in the region of intestinal stem cells. Mice expressing Nos2 did not show these changes. These mice did, however, show an arginine-dependent increase in colon tumor number and incidence, while no effect on apoptosis was seen. These changes were associated with increased nitrotyrosine formation in epithelial cells. Mice lacking Nos2 did not show changes in tumorigenesis or nitrotyrosine formation, while demonstrating an arginine-dependent increase in apoptosis. These data suggest that Nos2 and dietary arginine have significant effects on intestinal and colonic tumorigenesis in Min mice. In both tissues, loss of Nos2 is associated with decreased tumorigenesis when mice are supplemented with dietary arginine. In the small intestine, Nos2 prevents the arginine-induced decrease in tumor number and size, which is associated with NOS3 expression and increased apoptosis. In the colon, Nos2 is required for the arginine-induced increase in tumor number and incidence.

Adenomatous Polyposis Coli Protein↗
PubMed2002

Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps.

To investigate angiogenesis during intestinal polyp development, we determined the microvessel density (MVD) in polyps of Apc knockout (Apc(Delta716)) mice, a model for human familial adenomatous polyposis. We scored MVD also in several compound mutants carrying Apc(Delta716), namely, mice with an additional mutation in Smad4, in which the polyps progress into invasive adenocarcinomas; mice with a cyclooxygenase (COX)-2 gene (Ptgs2) mutation, in which adenoma growth is suppressed; and mice with prostaglandin E(2) EP receptor gene mutations. In both simple Apc(Delta716) and compound Apc(Delta716) Smad4 mutants, MVD increased in a polyp size-dependent manner only in the polyps expanded beyond a threshold of about 1 mm in diameter. These results indicate that tumor angiogenesis is stimulated only after tumors grow to a certain size, and this angiogenic switch is common to both benign adenomas and malignant adenocarcinomas. In Apc(Delta716) polyposis attenuated by the COX-2 gene mutation, in contrast, MVD did not increase even in polyps larger than 1 mm. The same phenomenon was observed in the compound mutant mice with Apc(Delta716) and the EP(2) receptor gene mutations, but not in other EP compound mutants. We also immunohistochemically studied COX-2 and angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor. Interestingly, expression of these proteins was also increased in polyps larger than 1 mm. These results suggest that, in both benign and malignant mouse intestinal tumors, stromal expression of COX-2 results in elevated prostaglandin E(2) levels that stimulate cell surface receptor EP(2), followed by induction of vascular endothelial growth factor that causes tumor angiogenesis.

Adenocarcinoma↗
PubMed1996

Intractable constipation with a decrease in substance P-immunoreactive fibres: is it a variant of intestinal neuronal dysplasia?

After Hirschsprung's disease was ruled out for 25 children who had severe chronic constipation, the authors studied the distribution of immunoreactivity for substance P (SP) and vasoactive intestinal peptide (VIP) in the intestinal wall, using immunofluorescence. SP and VIP immunoreactivity identify excitatory and inhibitory nerve fibres, respectively. Full-thickness rectal biopsy specimens were unsatisfactory, so seromuscular biopsies of the caecum, transverse colon, and sigmoid colon were obtained (by laparoscopy and laparotomy; n = 10 patients). SP-immunoreactive fibres were markedly reduced in seven, with concomitant reduction of VIP-immunoreactive fibres in four. In two other patients, there was no obvious reduction in SP- or VIP-immunoreactive fibres. In a patient who subsequently was found to have multiple endocrine neoplasia type 2b, the myenteric plexus was markedly hyperplastic, with an increase in nerve cells and nerve fibres. VIP-immunoreactive fibres were increased, but SP-immunoreactive fibres were markedly decreased. Surgical options included proximal stoma, Malone operation, and subtotal colectomy with preservation of the rectum. Three children with subtotal colectomy have had improvement over short-term follow-up. The combination of seromuscular laparoscopic biopsies and immunofluorescence demonstration of neuropeptides may identify new variants of intestinal neuronal dysplasia than can be treated successfully with surgery.

Adenomatous Polyposis Coli↗
PubMed1992

The risk of upper gastrointestinal cancer in familial adenomatous polyposis.

Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.

Adenomatous Polyposis Coli↗
PubMed2002

Efficient induction of rat large intestinal tumors with a new spectrum of mutations by intermittent administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in combination with a high fat diet.

In the present study we have established novel intermittent protocols featuring a high fat (HF) diet for efficient induction of large intestinal tumors with a relatively small amount of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In protocol 1, F344 male rats were first fed a diet containing 400 p.p.m. PhIP for 2 weeks, followed by continuous administration of a HF diet without PhIP for 108 weeks. In protocol 2, 2 week PhIP treatments were repeated three times with 4 week intervals on the HF diet alone, followed by continuous feeding of the HF diet for 42 weeks. At termination of the experiments, 16 (3 of 19) and 45% (9 of 20) of the rats had developed a total of three and 13 large intestinal tumors with protocols 1 and 2, respectively. The tumor incidence in protocol 2 was comparable with that observed with continuous feeding of 400 p.p.m. PhIP for 52 weeks, after exposure to only approximately 10% of the amount of carcinogen. Five of nine (55%) tumors harbored mutations in either the beta-catenin or Apc gene, while all demonstrated accumulation of beta-catenin protein in the cytoplasm and nucleus. This suggests that other unknown genetic alterations in the Wnt-Apc-beta-catenin signaling pathway could have been involved in the development of tumors. By further modifying this intermittent protocol with HF diet, one could expect more efficient induction of lesions with much smaller amounts of PhIP in a shorter period. In addition, this model could provide a means to elucidate genetic alterations in large intestinal tumors induced by relatively low levels of carcinogenic insult, mimicking the cases of human colon carcinogenesis induced by exposure to environmental carcinogens.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Mlh1 deficiency enhances several phenotypes of Apc(Min)/+ mice.

Defects in APC and DNA mismatch repair genes are associated with a strong predisposition to colon cancer in humans, and numerous mouse strains with mutations in these genes have been generated. In this report we describe the phenotype of Min/+ Mlh1-/- mice. We find that these doubly mutant mice develop more than three times the number of intestinal adenomas compared to Min/+ Mlh1+/+ or +/- mice but that these tumors do not show advanced progression in terms of tumor size or histological appearance. Full length Apc protein was not detected in the tumor cells from Min/+ Mlh1-/- mice. Molecular analyses indicated that in many tumors from Min/+ Mlh1-/- mice, Apc was inactivated by intragenic mutation. Mlh1 deficiency in Min/+ mice also led to an increase in cystic intestinal crypt multiplicity as well as enhancing desmoid tumorigenesis and epidermoid cyst development. Thus, Mlh1 deficiency influences the somatic events involved in the development of most of the phenotypes associated with the Min mutation. Oncogene (2000).

Adaptor Proteins, Signal Transducing↗
PubMed1990

[Comparative evaluation of the anal sphincter function after sphincter-sparing operations in diffuse polyposis].

Experience in treating 76 patients who were subjected to various sphincter-preserving operations is analysed. It is shown that after subtotal resection of the large intestine with ++abdomino-anal resection of the rectum and pull-through of the right parts of the colon into the anal canal as well as after pull-through of the segment of the transverse colon into the anal canal, the neuro-reflex activity of the musculus sphincter ani internus is destroyed in 55% and reduces in 25% of patients while the reflex activity of the musculus sphincter ani externus is disturbed in 45% of patients and is not restored later. The results bear evidence that the condition of the rectal obturation apparatus does not depend on the segment of the colon subjected to the pull-through operation (cecum, ascending colon, transverse colon). Experience has shown that the results of sphicterometry, electromyography, and electromanometry in various periods after colectomy, mucosectomy of the rectum, and formation of ileorectal anastomosis are much better than those after pull-through operations on various parts of the colon, and return to normal values in 18 months.

Anal Canal↗
PubMed2004

Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice.

To determine its effect on intestinal tumorigenesis and the protumorigenic COX pathway in Apc(Min/+) mice, resveratrol was administered as a powdered admixture in the diet at 0, 4, 20, or 90 mg/kg body weight for 7 wk. In two separate experiments, resveratrol did not affect intestinal tumor load. It was stable in the diet under experimental conditions, circulated in the plasma as the glucuronide-conjugated form and reached the tumors as evidenced by significant decreases in PGE2 levels. However, immunohistochemical staining of intestinal tumors revealed no changes in COX-2 expression. This study demonstrates that resveratrol consumed ad libitum in the diet, does not modify tumorigenesis in Apc(Min/+) mice.

Adenomatous Polyposis Coli↗
PubMed1987

Colorectal cancer in patients with family history.

The relationship between first degree family history of colorectal cancer and some pathological and clinical features was investigated in 302 patients affected by large bowel carcinoma. Patients with inherited forms of polyposis of the large bowel were excluded. Thirty-six (11.9%) had at least one close relative affected by intestinal cancer. No relationship between family history and pathological features (anatomic distribution, stage and grading) was found. Moreover no difference in prognosis between patients with a family history and those without was shown. These results suggest no relationship between a first degree family history and the natural history of the disease.

Adult↗
PubMed2002

Sonographic diagnosis of multiple small-bowel intussusceptions in Peutz-Jeghers syndrome: a case report.

Peutz-Jeghers syndrome (PJS) is a rare, though well-described, hereditary polyposis syndrome associated with mucocutaneous pigmentation that typically presents in the second decade of life with complications related to intestinal polyps. We present two cases of teenaged girls presenting with small-bowel intussusceptions within a 3-month period. Sonographic examinations readily revealed small-bowel intussusceptions with secondary small-bowel obstruction. In both the symptoms were less severe than one would expect given the underlying pathology found at subsequent surgery. Sonographic imaging with pathologic correlation is provided.

Child↗
PubMed2005

Sulindac sulfide-induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2.

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that induces apoptosis in cultured colon cancer cells and in intestinal epithelia in association with its chemopreventive efficacy. Resistance to sulindac is well documented in patients with familial adenomatous polyposis; however, the molecular mechanisms underlying such resistance remain unknown. We determined the effect of ectopic Bcl-2 expression upon sulindac-induced apoptotic signaling in SW480 human colon cancer cells. Sulindac sulfide activated both the caspase-8-dependent and mitochondrial apoptotic pathways. Ectopic Bcl-2 attenuated cytochrome c release and apoptosis induction compared with SW480/neo cells. Coadministration of sulindac sulfide and the small-molecule Bcl-2 inhibitor HA14-1 increased apoptosis induction and enhanced caspase-8 and caspase-9 cleavage, Bax redistribution, and cytochrome c and second mitochondria-derived activator of caspase release. Given that sulindac sulfide activated caspase-8 and increased membrane death receptor (DR4 and DR5) protein levels, we evaluated its combination with the endogenous death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Coadministration of sulindac sulfide and TRAIL cooperatively enhanced apoptotic signaling as effectively as did HA14-1. Together, these data indicate that HA14-1 or TRAIL can enhance sulindac sulfide-induced apoptosis and represent novel strategies for circumventing Bcl-2-mediated apoptosis resistance in human colon cancer cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Sessile serrated adenoma: a brief history and current status.

Sessile serrated adenoma (SSA) is a polyp of the large intestine, which was first described in 1996. It presents as a solitary lesion or in a setting of a polyposis previously coined as "serrated adenomatous polyposis." The importance of correct recognition of this lesion and distinction from other serrated polyps of the colon is in that the newly described "serrated pathway" of colorectal carcinogenesis seems to apply mostly to SSA and not to other serrated polyps of the colon. This review describes the history of morphologic discovery of SSA and reports on current status of this lesion.

Adenomatous Polyps↗
PubMed2006

Intestinal overexpression of ZNF148 suppresses ApcMin/+ neoplasia.

ZNF148 (ZBP-89, Zfp148) is a multifunctional transcription factor expressed at low levels in most tissues. When overexpressed in gastrointestinal cancer cell lines, ZNF148 inhibits cellular proliferation and induces apoptosis. We sought to determine whether intestinal ZNF148 overexpression would abrogate adenoma development in the ApcMin/+ mouse, i.e., whether ZNF148 is a tumor suppressor. The 13-kb villin promoter was spliced upstream of the ZNF148 cDNA to generate transgenic villin-ZNF148 (ZNF148TgVZ) mice. Intestinal mucosal ZNF148 expression was elevated in four of five ZNF148(TgVZ) lineages and correlated with increased caspase-3 expression and activation. In addition, DNA fragmentation was increased in ZNF148TgVZ mice relative to wild-type littermates. These results suggested that increased intestinal ZNF148 expression induces apoptosis. ZNF148TgVZ mice were crossed with ApcMin/+ mice to assess the biological significance of intestinal ZNF148 overexpression. The presence of the ZNF148TgVZ allele in ApcMin/+ mice correlated with reduced gastrointestinal bleeding at 5 weeks, a 50% reduction in adenoma burden at 20-22 weeks, and prolonged survival (median survival of 33.5 days vs. 21.5 days), relative to nontransgenic littermates. These data suggest that enhanced ZNF148 expression activates intestinal apoptosis and thereby mitigates disease burden in ApcMin/+ mice. They also suggest that ZNF148 is a therapeutic target to inhibit colon cancer development.

Adenoma↗
PubMed1999

Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?

The hydrolysis of sphingomyelin generates key molecules regulating cell growth and inducing apoptosis. Data from animal cancer models support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. In the intestinal tract, a sphingomyelinase with an optimum alkaline pH has been identified. We recently found that the activity of alkaline sphingomyelinase is significantly decreased in colorectal adenocarcinomas, indicating a potential anticarcinogenic role of this enzyme. To further examine whether the reduction of sphingomyelinase is present already in the premalignant state of neoplastic transformation, we measured sphingomyelinase activities in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal tubulovillous adenomas. Tissue samples were taken from adenomas and surrounding macroscopically normal mucosa from 11 FAP patients operated with ileorectal anastomosis, from three FAP patients with intact colon, from 13 patients with sporadic colorectal adenomas and from 12 controls. Activities of acid, neutral and alkaline sphingomyelinase were measured together with alkaline phosphatase. In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05). Similar reductions were found in the surrounding mucosa. In sporadic adenoma tissue, only alkaline sphingomyelinase was reduced significantly, by 57% (P < 0.05). Alkaline phosphatase was not changed in FAP adenomas, but decreased in the sporadic adenomas. We conclude that the markedly reduced levels of alkaline sphingomyelinase activities in FAP adenomas and in the surrounding mucosa may be a pathogenic factor that can lead to unrestrained cell proliferation and neoplastic transformation.

Adenoma↗