UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We earlier showed that lovastatin potentiated the chemopreventive effects of sulindac against colon neoplasia in a rodent model and augments apoptosis induced by 5-FU and cisplatin in human colon cancer cells. In the present study, we investigated effects of lovastatin in spontaneously immortalized rat intestinal epithelial cells, IEC-18 and their K-ras transformed clones. Lovastatin induced morphologic changes (cell rounding and detachment) and apoptosis that were not influenced by K-ras mutations, but were prevented by geranylgeranyl-pyrophosphate or by mevalonate. Clostridium difficile toxin B, which directly inactivates rho, induced similar morphologic changes and apoptosis. Cycloheximide prevented these effects of lovastatin, but not C. difficile toxin B. Lovastatin decreased the amounts of membrane bound rhoA and rhoB. Cycloheximide and geranylgeranyl-pyrophosphate prevented lovastatin induced morphologic changes and apoptosis but did not inhibit lovastatin-induced changes in membrane translocation of rho. Our data suggest that lovastatin induces morphologic changes and apoptosis by inhibiting geranylgeranylation of small GTPases of the rho family and thereby inactivating them. Restoration of membrane translocation of rho is not necessary for preventing lovastatin-induced morphologic changes or apoptosis.
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PMID:Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. 1189 68

We experienced an unusual case of duodenal adenocarcinoma associated with Peutz-Jeghers syndrome (PJS). A 34-year-old woman was admitted to our hospital with abdominal pain. She had been diagnosed as having PJS at 21 years of age, based on the presence of mucocutaneous pigmentation of the lip and fingertips, and colonic hamartomatous polyps. Abdominal computed tomography revealed a tumor in the third portion of the duodenum extending into the pancreas head. As the tumor was pathologically determined to be adenocarcinoma at the time of surgery, pylorus-preserving pancreaticoduodenectomy was performed. We carried out molecular analyses of this patient to examine the pathway of carcinogenesis in PJS. The tumor did not show somatic mutation of the APC and K-ras genes, which is a critical step for the adenoma-carcinoma sequence in colon cancer. Importantly, a germline mutation of the STK11 gene was detected at codon 281 delC in exon 6. Moreover, the tumor showed loss of heterozygosity of the 19p marker near STK11 and somatic mutation of the p53 gene. These findings suggest that STK11 is a tumor suppressor gene regulating the development of hamartomas, and that somatic mutation of p53 subsequently promotes gastrointestinal cancer at a later stage in PJS.
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PMID:Duodenal cancer in a patient with Peutz-Jeghers syndrome: molecular analysis. 1205 37

A major obstacle to obtaining more detailed insights into the diversity of phenotypic and molecular changes occurring in colon cancer cells is the lack of low-passage colon cancer cell lines, which would still closely reflect the phenotype of the colon cancer cells in vivo. Here, we characterize eight novel, low passage number human colon carcinoma cell lines, originating from colorectal cancers extensively characterized in the clinics. All cell lines closely resemble the original tumors with respect to phenotype, markers and detectable genetic changes. Cell morphology and marker expression is highly variable, ranging from fully polarized cells correctly expressing all basolateral epithelial markers, to cells with mesenchymal characteristics and a complete loss of polarity due to delocalization or loss of junction complex proteins. The alterations in phenotype and epithelial marker expression correspond to changes already detectable in the primary tumor in vivo. Seven of the cell lines show chromosomal instability, while one cell line is characterized by microsatellite instability. p53 associated with K-ras mutations were detected in three cell lines. Hitherto non-described E-cadherin mutations were found at both alleles in one cell line whereas in another cell line the E-cadherin protein was down-regulated. A stabilizing beta-catenin mutation (S45F) appears in the same cell line that carried the mutated E-cadherin gene. Six cell lines carried APC mutations, which in five of the lines led to an activated beta-catenin/Tcf/LEF signaling pathway. In accordance with beta-catenin/Tcf/LEF activation, the cell lines show increased migration and invasiveness. Our results show that the characterized, low-passage cell lines mirror the diversity of the individual tumors from which they were derived. Through molecular analyses of these cell lines we demonstrate that tumorgenicity events are much more diverse in human colon cancer than expected, despite the common origin of the tumors from a small patient group with similar tumor grading and clinical prognosis.
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PMID:Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers. 1209 41

K-ras mutation is the most common oncogenic alteration in various human cancers including colorectal carcinomas. Point mutations have the potential to activate the K-ras gene if they occur in the critical coding sequences. Almost all of these mutations have been localized in codons 12, 13 and 61. We report a case of colon cancer presenting point mutations at both codons 12 and 22 of the K-ras gene. PCR-SSCP and subsequent sequencing revealed that GGT (glycine, wild-type) to AGT (serine) substitution at codon 12 and CAG (glutamine, wild-type) to CGG (arginine) substitution at codon 22 occurred in the same allele.
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PMID:Concurrent mutations of K-ras oncogene at codons 12 and 22 in colon cancer. 1211 Jun 40

To elucidate early molecular events related to colon carcinogenesis, we examined alterations in the expression of colon cancer-related genes such as cyclooxygenase (COX)-2, APC and c-Myc, cell proliferation and apoptosis in the background colon mucosa, and K-ras mutation at aberrant crypt foci (ACF) in the colons of azoxymethane (AOM)-treated rats 4 weeks after the first exposure to AOM. About 40 ACF/colon were induced in the colons of rats treated with AOM (Group 1); however, rats not treated with AOM (Group 2) showed no ACF formation in the colon. The level of AgNORs in the colonic mucosa was significantly higher in Group 1 than in Group 2 (P<0.01). The colonic mucosa in Group 1 looked macroscopically and histologically normal, but the proliferative activity of the mucosa of rats treated with AOM was clearly elevated. COX-2 mRNA expression was not detected in normal colonic mucosa in Group 2, but 3 out of 10 rats in Group 1 showed COX-2 mRNA expression in their colons by reverse transcription (RT)-polymerase chain reaction (PCR). There was a tendency toward an increased expression level of COX-2 in the AOM-treated group. The level of APC mRNA expression in Group 1 was significantly lower than that in Group 2 (P<0.01). Moreover, the level of c-Myc mRNA expression in Group 1 was significantly higher than that in Group 2 (P<0.01). An average of 0.034+/-0.006% apoptosis in colonic mucosa was detected in Group 1; the incidence of apoptosis in Group 2 was 0.021+/-0.005%. The difference between Groups 1 and 2 was significant (P<0.01). These results indicate that apoptosis was possibly induced to eliminate cells damaged by AOM administration. Six out of 22 (27%) ACF with 4 or more crypts showed K-ras mutations at codon 12; all mutations were G to A transitions (GGT to GAT). ACF with 1-3 crypts showed no mutations in the K-ras gene. In conclusion, AOM caused an increase in COX-2 and c-Myc mRNA expression, a decrease in APC mRNA expression, induction of apoptosis in normal-appearing colonic mucosa, and a K-ras mutation in ACF with 4 or more crypts. These findings may help to identify key targets in the early steps of colon carcinogenesis, against which drugs that would be broadly effective for chemoprevention of colon cancer could be developed.
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PMID:Molecular changes in the early stage of colon carcinogenesis in rats treated with azoxymethane. 1214 79

Polyamines are downstream mediators of genetic risk factors in human intestinal cancers. The adenomatous polyposis coli (APC) tumour-suppressor gene, which is mutated in essentially all human colon cancers, regulates the expression of several e-box transcription factors. These factors, in turn, regulate the transcription of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. The Kirsten ras ( K-ras ) oncogene regulates the expression of several genes, including suppressing the expression of peroxisomal proliferator-activated receptor gamma (PPARgamma). This PPAR, in turn, activates the expression of the spermidine/spermine-N(1)-acetyltransferase (SSAT), the first enzyme in polyamine catabolism. The non-steroidal anti-inflammatory drug (NSAID) sulindac induces the transcription of SSAT via activation of PPARgamma. Inactivation of the APC tumour-suppressor gene, and the activation of K-ras, have a combined effect on increasing tissue polyamine contents due to increased synthesis and decreased catabolism of the polyamines. Pharmacological strategies for suppressing ODC (e.g. the enzyme-activated inhibitor alpha-difluoromethylornithine) and activating SSAT (e.g. NSAIDs) are potent inhibitors of intestinal carcinogenesis in rodent models. Clinical trials combining these classes of agent in humans with risk factors for colon cancer are in progress.
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PMID:Polyamines as modifiers of genetic risk factors in human intestinal cancers. 1265 45

Cigarette smoking has been inconsistently associated with colon cancer risk. To evaluate the hypothesis that smoking is primarily linked to a specific colon tumor subgroup(s), we assessed associations between smoking and the occurrence of mutations in the APC, K-ras and p53 genes, p53 overexpression, and microsatellite instability (MSI) in a Dutch population-based case-control study on sporadic colon carcinomas. The study population consisted of 176 cases and 249 controls. Smoking status (never, ever), number of cigarettes smoked per day (never, <15, > or =15), total years of smoking (never, < or =30, >30), and years since first started smoking (never, < or =35, >35) were all evaluated. Cigarette smoking status was significantly differently related to p53 overexpression-positive (p53(pos)) tumors compared with p53 overexpression-negative (p53(neg)) tumors (p53(pos) versus p53(neg), OR 0.4, 95% CI 0.2-0.9), as well as to tumors with transversion mutations in APC, K-ras or p53 (transv(+)) compared with tumors without transversion mutations in one of these genes (transv(-)) (transv(+) versus transv(-), OR 2.5, 95% CI 1.0-5.9). Positive associations were observed with p53(neg) tumors and transv(+) tumors when compared with the population-based controls (ever versus transv(-), OR 1.5, 95% CI 0.9-2.8 and OR 2.2, 95% CI 0.9-5.6, respectively), inverse associations with p53(pos) tumors and transv(-) tumors (ever versus never, OR 0.5, 95% CI 0.3-1.0 and OR 0.8, 95% CI 0.5-1.3, respectively). Similar patterns of association were observed for the other smoking variables evaluated. In addition, although statistically non-significant, smoking was more notably positively associated with tumors that exhibit K-ras mutations, especially K-ras transversion mutations, than with tumors without K-ras mutations. An inverse relationship between smoking and the occurrence of APC mutations was suggested, whereas no clear associations were observed with MSI. Our data suggest that smoking-related colon cancers develop through a p53(neg) pathway and that smoking particularly results in colon carcinomas with transversion mutations.
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PMID:Cigarette smoking and genetic alterations in sporadic colon carcinomas. 1266 19

The drs gene was originally isolated as a transformation suppressor gene against the v-src oncogene. Expression of drs mRNA is down-regulated by retroviral oncogenes such as v-src and v-K-ras in the rat cell line F2408. Expression of drs mRNA is also markedly reduced in a variety of human cancer cell lines, including those of carcinomas of the colon, bladder, and ovary, suggesting that down-regulation of drs mRNA is correlated with the development of human cancers. To clarify the correlation between down-regulation of the drs gene and malignant tumor formation in human colorectal neoplasms, we examined expression of drs mRNA in a variety of colon cancer tissues by in situ hybridization. A total of 53 morphologically distinct neoplastic specimens were divided into the following five groups according to morphology: low and high grade adenoma in 7 and 12 cases, respectively (groups A, B), protruded-type carcinoma in 16 (group C), superficial-type carcinoma with an adenomatous component in 10 (group D) or superficial-type carcinomas without any adenomatous component in 8 (group E). Expression of drs mRNA was detected in normal mucosa, low-grade adenoma and most superficial-type carcinomas without any adenomatous component. On the other hand, the rate of drs mRNA expression was significantly lower in protruded-type adenocarcinoma and superficial-type carcinoma with an adenomatous component. Our results indicate that down-regulation of drs mRNA is closely correlated with carcinomas which arise from adenomatous polyps in the course of the adenoma-carcinoma sequence, but that most carcinomas arising de novo are independent of the tumor suppressor function of the drs gene.
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PMID:Down-regulation of drs mRNA in colorectal neoplasms. 1271 66

K-ras mutations occur frequently in colon cancer and contribute to autonomous growth. In the azoxymethane (AOM) model of colon cancer, in addition to K-ras mutations, we have shown that wild-type (WT) Ras can be activated by upstream pathways, including, e.g., signaling by ErbB receptors. Tumors with mutant or activated WT Ras had increased cyclooxygenase-2 (Cox-2) expression. We have also shown that ursodeoxycholic acid (UDCA) prevented AOM-induced colon cancer and suppressed Cox-2 induction. In this study, we examined the role of Ras in Cox-2 inhibition by UDCA. Rats were fed AIN-76A chow alone, or supplemented with 0.4% UDCA, and received 20 mg/kg AOM i.p. weekly x 2 weeks. At 40 weeks, rats were sacrificed, and tumors were harvested. K-ras mutations were assessed by primer-mediated RFLP, allele-specific oligonucleotide hybridization, and direct DNA sequencing. Ras was immunoprecipitated and defined as activated if [Ras - GTP/(Ras - GTP + Ras - GDP)] was >3 SD above normal colonocytes. Cox-2 mRNA was determined by reverse transcription-PCR, and protein expression was assessed by Western blotting and immunostaining. In the AOM alone group, Ras was activated by mutations in 8 of 30 (27%) tumors, and WT Ras was activated in 7 of 30 (23%) tumors. UDCA significantly suppressed the incidence of tumors with mutant Ras (1 of 31, 3.2%; P < 0.05) and totally abolished the development of tumors with activated WT Ras (0 of 10; P < 0.05). In the AOM alone group, Cox-2 was up-regulated >50-fold in tumors with normal Ras activity and further enhanced in tumors with mutant or signaling-activated Ras. UDCA significantly inhibited Cox-2 protein and mRNA levels in tumors with normal Ras activity. In summary, we have shown for the first time that UDCA suppressed the development of tumors with Ras mutations and blocked activation of WT Ras. Furthermore, UDCA inhibited Cox-2 induction by Ras-dependent and -independent mechanisms.
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PMID:Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. 1283 36

Since the first detection of aberrant crypt foci (ACF) in carcinogen-treated mice, there have been numerous studies focusing on these microscopically visible lesions both in rodents and in humans. ACF have been generally accepted as precancerous lesions in regard to histopathological characteristics, biochemical and immunohistochemical alterations, and genetic and epigenetic alterations. ACF show variable histological features, ranging from hyperplasia to dysplasia. ACF in human colon are more frequently located in the distal parts than in the proximal parts, which is in accordance with those in colorectal cancer (CRC). The immunohistochemical expressions of carcinoembryonic antigen (CEA), beta-catenin, placental cadherin (P-cadherin), epithelial cadherin (E-cadherin), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and P16INK4a are found to be altered. Genetic mutations of K-ras, APC and p53, and the epigenetic alterations of CpG island methylation of ACF have also been demonstrated. Genomic instabilities due to the defect of mismatch repair (MMR) system are detectable in ACF. Two hypotheses have been proposed. One is the "dysplasia ACF-adenoma-carcinoma sequence", the other is "heteroplastic ACF-adenoma-carcinoma sequence". The malignant potential of ACF, especially dysplastic ACF, makes it necessary to reveal the nature of these lesions, and to prevent CRC from the earliest possible stage. The technique of magnifying chromoscope makes it possible to detect "in vivo" ACF, which is beneficial to colon cancer research, identifying high-risk populations for CRC, and developing preventive procedures.
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PMID:Aberrant crypt foci as microscopic precursors of colorectal cancer. 1466 4

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