Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little is known about the the signalling pathways driving the adenoma-to-carcinoma sequence in human colonic epithelial cells. Accumulation and activation of the src tyrosine kinase in colon cancer suggest a potential role of this oncogene in this early progression. Therefore, we introduced either activated src (m-src), polyoma-MT alone or combined with normal c-src in the adenoma PC/AA/C1 cell line (PC) to define the function and phenotypic transformations induced by these oncogenes in familial adenomatous polyposis (FAP) colonic epithelial cells. Functional expression of these oncoproteins induced the adenoma-to-carcinoma conversion, overexpression of the hepatocyte growth factor (HGF) receptor Met, but failed to confer invasiveness in vivo and in vitro, or to produce alterations in cell proliferation and differentiation. In contrast, PC-msrc cells became susceptible to the HGF-induced invasion of collagen gels and exhibited sustained activation of the pp60src tyrosine kinase and Tyr phosphorylation of the 120-kDa E-cadherin, which was further increased by HGF Transcripts of HGF were clearly identified by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot in the parental and transformed PC cells, suggesting an autocrine mechanism. Taken together, the data indicate that: (1) experimental activation of src and PyMT pathways directly induces tumorigenicity and Met upregulation in a colon adenoma cell line; (2) HGF-activated Met and src cooperate in inducing invasion; (3) in view of the molecular associations between catenins and cadherin or the tumour-suppressor gene product APC, the cell adhesion molecule E-cadherin may constitute a downstream effector of src and Met.
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PMID:Progression of familial adenomatous polyposis (FAP) colonic cells after transfer of the src or polyoma middle T oncogenes: cooperation between src and HGF/Met in invasion. 901 33

Loss of function of both alleles of the APC gene results in colorectal adenoma formation in familial adenomatous polyposis, an autosomal dominant genetic disorder leading to multiple colorectal tumors at an early age. Previous molecular studies indicate that the mutant cells forming dysplastic epithelium within adenomas are clonally derived. We show, using immunostaining and molecular techniques, that the dysplastic epithelium of adenomas actually contains a mixture of cells derived from both mutant and normal stem cells. Well-differentiated mucous cells in the dysplastic epithelium, one of the indicators of severity of dysplasia, were derived from normal stem cells. Carcinomas in these patients, in contrast, contained only mutant cells, indicating that the subsequent mutations incurred by these cells have led to their isolation from the normal population.
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PMID:Clonality of dysplastic epithelium in colorectal adenomas from familial adenomatous polyposis patients. 901 54

Activating mutations in the Ki-ras2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer-free bowel do not share this high incidence of Ki-ras mutations. This difference in mutation incidence between adenomas from cancer-free and cancer-bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer-bearing bowel, however, are particularly liable to carry Ki-ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki-ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer-prone individuals may suffer more mutational events than those in persons selected as cancer-free.
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PMID:Ki-ras mutations in adenomas: a characteristic of cancer-bearing colorectal mucosa. 961 89

Dysplastic colon adenomas are thought to arise from growth of clones of APC -/- colonic epithelial cells. Isolated clusters of dysplastic crypts are often observed in patients with familial adenomatous polyposis. These patients have genotype APC +/-, and the clusters of dysplastic crypts (called microadenoma or aberrant crypt foci) are thought to represent an early stage in the expansion of a mutant clone of APC -/- cells. It is thought that the growth of these clusters of mutant crypts results from crypt replication through a process similar to what occurs in the normal crypt cycle. We measured the relative replication rate of mutant crypts by analyzing the size of clusters of mutant crypts in APC +/- individuals and found that mutant APC -/- crypts replicate more rapidly than do normal APC +/- (i.e., nonneoplastic) crypts. In contrast, the replication rate of mutant crypts in Apc +/- mice is not significantly different from that of normal crypts, thus supporting previous findings that aberrant crypt foci do not contribute significantly to the colon adenoma population in adult Apc +/- mice. Intriguingly, we found an effect of Apc heterozygosity on the frequency of branching crypts in young mice.
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PMID:APC mutation and the crypt cycle in murine and human intestine. 906 Aug 21

Genetic epidemiology studies of colorectal cancer (CRC) can identify persons who are at inordinately high risk and who thereby might benefit from targeted early detection and primary prevention programs, inclusive of prophylactic surgery in selected cases. The discipline of molecular genetics has identified germline mutations that include APC in familial adenomatous polyposis (FAP) and mutator genes, namely MSH2, MLH1, PMS1, and PMS2 in hereditary nonpolyposis colorectal cancer (HNPCC). These discoveries have significantly enhanced our ability to identify individuals whose cancer destiny can literally be determined at birth. This review updates HNPCC's differential diagnosis, heterogeneity, tumor spectrum, newly found evidence of accelerated colonic adenoma to CRC, survival advantage, and currently available surveillance and management programs. Emphasis has been on how knowledge of the genetics and natural history of HNPCC can be used effectively to promote early diagnosis or prevention of cancer.
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PMID:An update of HNPCC (Lynch syndrome). 906 84

In this study we sought factors that determine the survival of human colonic epithelial cells. Normal colonic epithelial cells are dependent on cell-cell contacts and survival factors for the inhibition of apoptosis whereas, during colorectal tumorigenesis, cells develop mechanisms to evade these controls. The ability to survive loss of cell-cell contacts and/or growth factor deprivation is a marker of tumour progression. Many adenoma (premaligant) cultures survive only if cell-cell contacts are maintained in vitro and die by apoptosis if trypsinized to single cells. This also occurs in adenomas derived from familial adenomatous polyposis (FAP) patients, therefore APC mutations do not confer resistance to cell death in response to loss of cell-cell contacts. We show here that if cell-cell contacts are maintained such cells are capable of survival in suspension. Adenoma cells also undergo apoptosis in response to removal of serum and growth factors from the medium. After removal of serum and growth factors c-myc is down-regulated within 2 h. Therefore, the induction of apoptosis is not an inappropriate response of the cells due to a deregulated c-myc gene. The apoptotic response is also p53 independent. Such cultures have been used to determine specific survival factors for colonic epithelial cells. Insulin, the insulin-like growth factors I and II, hydrocortisone and epidermal growth factor (EGF) protect cells from the induction of apoptosis in the absence of serum over a short-term period of 24 h. This approach may give insight into the factors governing growth and survival of colonic epithelial cells in vivo. This is the first report of specific growth factors protecting against apoptosis in human colonic epithelial cells.
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PMID:Cell-cell contact and specific cytokines inhibit apoptosis of colonic epithelial cells: growth factors protect against c-myc-independent apoptosis. 908 30

Germline mutations of the putative tumor suppressor gene APC are associated in high frequency with the familial adenomatous polyposis, predisposing the patients to colorectal neoplasia. Similarly, sequence analyses have revealed that in more than half of patients with sporadic colorectal carcinoma or adenoma, the APC gene was mutated. By employing genomic sequencing, i.e., base-specific analysis of methylated cytosines, we show here that the promoter region of the APC gene is heavily methylated at CpG sites in patients with colorectal carcinoma in comparison with normal colonic mucosa and premalignant adenomas. Our results suggest that cytosine methylation of the regulatory sequences of the APC gene could be involved in the progression of human colorectal cancer.
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PMID:Hypermethylation of the APC (adenomatous polyposis coli) gene promoter region in human colorectal carcinoma. 909 43

Advances in molecular biology have identified two important genes responsible for the hereditary colorectal cancers familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer. They are the APC gene and mismatch repair genes. The role of these genes in colorectal carcinogenesis has been studied intensively. The adenoma-carcinoma sequence was initially proposed by Vogelstein, and the multistep carcinogenesis theory is now well accepted. The various functions of the APC gene have been elucidated. APC genes are considered to play a role in shedding of the epithelial cells into the lumen. The mechanism behind formation of a unicryptal adenoma is now better understood. Adenoma formation is a monoclonal event with two hits of the APCgene. There is no zonal extension of the proliferative zone in the background colonic mucosa of FAP patients. In addition to the adenoma-carcinoma sequence, there seem to be various carcinogenetic pathways in the development of colorectal cancer. A depressed type of early cancer was recently found by the use of magnifying endoscopy. The incidence of K-ras mutation was extremely low in this group of early cancers. Some of the minute cancers show the p53mutation before the occurrence of APC mutation. Cancers of microsatellite mutator phenotype show exaggerated genomic instability at simple repeat sequences, such as TGFbetaRII. These genes may play a suppressor role in a p53 independent pathway of colorectal carcinogenesis. We are now in an exciting era of this progressing field of science. This genetic information may be more widely applicable clinically in the near future (e.g., for presymptomatic diagnosis, selection of patients for the most appropriate treatments, and assessment of malignant potential).
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PMID:Recent advances in molecular genetics of colorectal cancer. 927 97

We used the C57BL/6J-APC(Min)/+ mouse (Min mouse) to evaluate the chemopreventive effects of R-flurbiprofen (R-FB), the noncyclooxygenase-inhibiting enantiomer of FB. Weanling Min mice were administered 6 weeks of oral treatment with R-FB using 2.5-25 mg/kg of R-FB once per day (q.d.), 2.5-10 mg/kg of R-FB twice per day (b.i.d.), and 5 mg/kg of R-FB b.i.d. challenged with a high saturated fat diet. At necropsy we determined tumor and ulcer numbers, tumor size, and plasma levels of R- and S-FB. A linear dose response was observed from 2.5 to 10 mg/kg of R-FB, regardless of whether the drug was administered as a single or divided dose. Reductions in tumor number were significant (P < or = 0.02) for doses of R-FB from 2.5 to 25 mg/kg/day. A dose of 5 mg/kg R-FB b.i.d. was able to overcome the doubling in tumor number associated with the high saturated fat diet. At 20 and 25 mg/kg/day R-FB, we obtained the maximum response with up to 90% inhibition of total tumor number. At these doses, however, there was toxicity and animal deaths. This toxicity was associated with ulceration, presumably resulting from the in vivo epimerization of R- to S-FB that occurs in the mouse. Thus, we evaluated the oral pharmacokinetics of R-FB and its conversion to S-FB in wild-type mice. These kinetics experiments revealed inversion rates of 7.3 and 11.0% for the 2.5 and 10 mg/kg R-FB doses, respectively. S-FB administered alone (0.5 and 2.0 mg/kg q.d.), in doses mimicking the concentrations of S-FB associated with the R to S epimerization of the doses of R-FB used in our experiments, had little or no antitumor efficacy (P > 0.05). Thus, we conclude that R-FB itself, not the S-FB resulting from epimerization in the mouse, inhibits adenoma formation in the Min mouse. In humans, where there is no R to S epimerization, it is possible that larger doses of R-FB can be used without causing cyclooxygenase inhibition and its resulting ulcerogenicity and other side effects. To assess the effect of R-FB on established adenomas, we allowed 40 Min mice to remain untreated until 70 days of age (the time of necropsy in the previous experiments) and then treated them for an additional 42 days with 10 mg/kg R-FB q.d. or 5 mg/kg R-FB b.i.d.. Both drug-treated groups demonstrated tumor numbers significantly less than that of the vehicle control (P < 0.01). Our results suggest that prophylaxis and treatment trials of R-FB should be extended to humans.
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PMID:R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APC(Min)/+ mouse model: implications for prophylaxis and treatment of colon cancer. 933 Oct 93

Seven-week-old Apc1638N mice were exposed to a single dose of 5 Gy total-body X-irradiation resulting in a 8-fold increase in the number of intestinal tumors and a reduction of the lifespan to an average of 6 months. The distribution of tumors along the intestinal tract as well as the adenoma/carcinoma ratio, were similar between non-irradiated and irradiated animals. Semi-quantitative PCR analysis of intestinal-tumor DNA revealed that 10 out of 14 tumors had lost the wild-type Apc allele. However, in contrast to spontaneous Apc1638N intestinal tumors in which the LOH event at the Apc locus involves the entire chromosome 18 (1), in 6 out of 10 tumors derived from X-irradiated animals the Apc loss is associated with only a partial intrachromosomal deletion. The remaining tumors have lost all chromosome 18 markers tested. In addition to the intestinal tumors, female Apc1638N mice are susceptible to the development of mammary tumors. Upon X-irradiation, Apc1638N mice show a striking 15-fold increase in mammary tumors. Moreover, Apc1638N mice spontaneously develop other extra-intestinal neoplasia, such as desmoid-like lesions similar to those associated with familial adenomatous polyposis (FAP), the human syndrome caused by germline mutations in the APC gene. Spontaneous desmoid growth is sex-dependent, as male Apc1638N mice develop 3-fold more desmoids than female mice. Interestingly, X-irradiation seemed to increase the number of desmoids per animal nearly twofold only in female Apc1638N mice. Five out of 9 desmoids found in Apc1638N mice exposed to X-ray displayed loss of the wild-type Apc allele.
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PMID:Intestinal and extra-intestinal tumor multiplicities in the Apc1638N mouse model after exposure to X-rays. 939 21


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