transforming-growth-factor-beta and Adenomatous-Polyps

Transforming growth factor-beta1 (TGFbeta1) is a multifunctional signalling molecule with a wide array of roles. Animal experiments suggest that TGFbeta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting malignant transformation of those growths that do develop. A polymorphism in the signal peptide sequence of the TGFbeta1 gene (L10P) has been associated with increased levels of plasma TGFbeta1 in individuals with the P allele.. We investigated whether this polymorphism was associated with the risk of colorectal adenomatous or hyperplastic polyps in a case-control study of individuals from Minnesota. Risk of colorectal polyps was evaluated separately for individuals with adenomatous polyps (n = 513) and hyperplastic polyps (n = 191) relative to polyp-free controls (n = 606) using logistic regression analysis.. No overall association was seen between the L10P polymorphism and risk of colorectal adenomatous polyps. The age- and sex-adjusted odds ratios (OR) of developing colorectal hyperplastic polyps were 1.0 (95% CI: 0.7, 1.4) and 0.7 (95% CI: 0.4, 1.1) for individuals with the LP and PP genotypes, respectively, compared with individuals with the LL genotype. When stratified by smoking, evidence for a decreased risk of hyperplastic polyps associated with the P allele was seen only among ever smokers (P for trend = 0.05).. Whereas adenoma risk did not vary by TGFbeta1 L10P genotype, these results suggest that the L10P variant allele may have a protective role in the development of colorectal hyperplastic polyps, possibly consistent with its role as an inhibitor of epithelial growths.

Topics: Adenomatous Polyps; Adult; Age Distribution; Aged; Case-Control Studies; Colonic Polyps; Colorectal Neoplasms; Female; Genetic Predisposition to Disease; Genotype; Humans; Hyperplasia; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Smoking; Transforming Growth Factor beta; Transforming Growth Factor beta1

Serrated adenomas, hyperplastic polyps, and admixed hyperplastic/adenomatous polyps form a distinct group of colorectal tumors, the molecular genetic basis of which is still poorly understood. We describe a novel mouse model for serrated adenomas and mixed polyposis, here referred to as Sad (serrated adenomas), caused by a spontaneously risen splice site mutation in the murine Smad4 gene. The Sad chromosomal region was identified by genetic linkage and loss of heterozygosity (LOH) analysis. Subsequently, several candidate genes were investigated by expression and mutation analysis. By use of genetic linkage and LOH analysis, we mapped the Sad candidate to mouse chromosome 18, 44-48 cM, syntenic to human chromosome band 18q21. Within this chromosomal interval, the Smad2, Smad4, and Smad7 genes were analyzed for the presence of a disease-causing mutation in affected animals. A single nucleotide (nt) deletion was identified in the intron 5/exon 6 splice acceptor site of the Smad4 gene. The single base deletion results in a frameshift and an early termination codon through activation of a cryptic splice site 4 nt downstream in exon 6. The resulting mRNA is unstable, and the Sad mutation is thus likely to represent a null allele. Identification of a Smad4 mutation in the Sad mouse model provides further support for the involvement of the Smad genes, and thus the TGFB pathway, in the serrated/hyperplastic route to colorectal cancer.

Topics: Adenomatous Polyps; Animals; Cell Line; Colonic Polyps; Colorectal Neoplasms; Disease Models, Animal; DNA-Binding Proteins; Female; Fetal Death; Gene Expression Profiling; Genes, Lethal; Homozygote; Hyperplasia; Loss of Heterozygosity; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; RNA Splice Sites; Sequence Deletion; Signal Transduction; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor beta (TGF-beta) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia.. We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures.. MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes.. This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.

Topics: Adenoma; Adenomatous Polyps; Alleles; Carcinoma; Cell Line, Tumor; Cohort Studies; Colorectal Neoplasms; Cytokines; Disease-Free Survival; Female; Genotype; Growth Differentiation Factor 15; Humans; Immunohistochemistry; Logistic Models; Lymphocytes; Male; Neoplasm Metastasis; Prognosis; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Up-Regulation

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine and is thought to be involved in colorectal tumorigenesis as a regulator of cell growth and differentiation. This role is mainly supported by in vitro studies while its role in vivo remains unclear. The aim of the present study was to investigate whether the TGF-beta 1 precursor (beta 1-LAP) and the latent TGF-beta 1 binding protein (LTBP) are expressed in colorectal adenomas, the presumed precursors of most of colorectal adenocarcinomas. TGF-beta 1 precursor and LTBP were examined in 35 adenomas and 10 normal colonic mucosa specimens by immunohistochemistry, using specific polyclonal antibodies. In normal colonic mucosa, beta 1-LAP was moderately expressed in epithelial crypt cells and in the stromal cells in the lamina propria. In adenomas, beta 1-LAP was localized in epithelial cells with an heterogeneous pattern and was also present in stromal cells around the adenomatous glands. LTBP was not detected in epithelial cells but was observed in stromal cells and in the extracellular matrix (ECM). beta 1-LAP expression in epithelial cells did not correlate with the grade of dysplasia, while LTBP localized in stromal cells and ECM appeared to be closely associated with areas of higher grade of dysplasia. This study is the first demonstration of both beta 1-LAP and LTBP in colorectal adenomas with different dysplasia grades. Our results suggest that TGF-beta 1 might be involved in the mechanisms controlling in vivo colorectal tumorigenesis and support a role for the stromal-associated TGF-beta 1.

Topics: Adenomatous Polyps; Carrier Proteins; Colorectal Neoplasms; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Peptide Fragments; Protein Precursors; Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1