Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.
 ...
PMID:Obese state leads to elevated levels of TGF-beta and COX isoforms in platelets of Zucker rats. 1647 87

Bone morphogenetic protein (BMP), a member of the TGF-beta superfamily, is involved in development, morphogenesis, cell proliferation and apoptosis. Dysregulation of BMP signaling has been suggested in tumorigenesis. In an analysis of human colon normal mucosa and tumors at different stages by immunohistochemistry, we observed that the intensity of BMP-4 staining in late-adenocarcinomas was stronger than that in normal mucosa and adenomas, while there was no difference in the staining of its receptors (BMPR-IA and BMPR-II) at all stages. The up-regulation of BMP-4 was further validated in another panel of tumor tissues by real-time RT-PCR, showing that BMP-4 mRNA levels in primary colonic carcinomas with liver metastasis were significantly higher than that in the matched normal mucosa. In order to understand the functional relevance of BMP-4 expression in colon cancer progression, BMP-4-overexpressing cell clones were generated from HCT116 cells. Overexpression of BMP-4 did not affect the HCT116 cell growth. The cells overexpressing BMP-4 became resistant to serum-starvation-induced apoptosis and exhibited enhanced migration and invasion characteristics. Overexpression of BMP-4 changed cell morphology to invasive spindle phenotype and induced the expression and activity of urokinase plasminogen activator (uPA). These results indicate that BMP-4 confers invasive phenotype during progression of colon cancer.
 ...
PMID:Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. 1727 10

Mice deficient in the G-protein alpha subunit G(i)alpha(2) spontaneously develop colitis and colon cancer. IL-11 is a pleiotropic cytokine known to protect the intestinal epithelium from injury in animal models of colitis and is produced by subepithelial myofibroblasts in response to inflammatory mediators including TGF-beta, IL-1beta, and PGE(2). Arachidonic acid release and subsequent PGE(2) production is significantly decreased in the colonic mucosa of G(i)alpha(2)-/- mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in G(i)alpha(2)-/- mice despite the presence of mild colitis. Primary cultures of G(i)alpha(2)-/- intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF-beta or IL-1beta-stimulated IL-11 mRNA and protein than wild-type cells. Inhibitors of ERK or p38 MAPK activation dose dependently inhibited IMF and CMF IL-11 production in response to TGF-beta stimulation, whereas 16,16 dimethyl-PGE(2) and prostanoid receptor subtype-selective agonists induced IL-11 production. Treatment of animals with the EP4-specific agonist ONO-AE1-329 resulted in enhanced mucosal levels of IL-11, and increased IL-11 production by ex vivo cultured CMF. Modulation of cAMP levels produced diverging results, with enhancement of TGF-beta-induced IL-11 release in IMF pretreated with 8-Br-cAMP and inhibition in cells treated either with pertussis toxin or the PKA inhibitor H-89. These data suggest a physiological role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.
 ...
PMID:Decreased MAPK- and PGE2-dependent IL-11 production in Gialpha2-/- colonic myofibroblasts. 1733 78

The idea of generating cytotoxic T-lymphocytes that have anti-tumor activity has been the focus of many clinical trials aimed at delivering effective immunotherapy to cancer patients. We have gained insight into the human immune system in cancer patients as a result of these numerous clinical investigations. It is now clear that although various vaccination methods are capable of inducing tumor antigen-specific T-cells in the circulating blood, these immunological responses are infrequently correlated with clinical responses. Therefore, it appears that priming of a T-cell response is not sufficient for tumor regression and other avenues, downstream of the priming phase, need to be investigated. Mechanisms of immune evasion at the effector phase of the anti-tumor phase are currently under investigation, with an increasing focus on the tumor microenvironment. There is evidence indicating that multiple variables may contribute to immune escape, including: regulatory cells; inhibitory ligands on tumor cells, such as PD-L1 and B7x; soluble factors such as TGF-beta and IL-10; and nutrient-catabolizing enzymes, such as indoleamine-2,3-dioxygenase (IDO). In addition, there are ongoing efforts to assess the presence and function of effector cells within the tumor microenvironment. Tumor infiltrating lymphocytes (TILs) have been observed in patients with melanoma, colon cancer, and ovarian cancer. TILs in these patients have been associated with favorable clinical outcomes. In the clinical setting of bladder cancer, as compared to melanoma, there is limited data regarding TILs. This review will focus on immunological responses to bladder cancer and ongoing studies to identify factors that are amenable to therapeutic manipulation.
 ...
PMID:Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer. 1759 43

TGFBR1*6A is a common hypomorphic variant of the type I transforming growth factor (TGF)-beta receptor (TGFBR1), which transduces TGF-beta growth inhibitory signals less effectively than TGFBR1. Recent studies suggest that TGFBR1*6A confers a selective growth advantage to both normal appearing and cancerous epithelial cells in the presence of TGF-beta. We have previously shown that TGFBR1*6A is somatically acquired in head and neck and colon cancer (10). Using microdissected tissues, we show that TGFBR1*6A is somatically acquired by stromal and epithelial cells adjacent to colorectal and head and neck tumors. Somatic acquisition of the TGFBR1*6A allele is not accompanied by acquisition of other tumor-specific mutations. Furthermore, lymphocytes located within the stroma or the normal appearing epithelium do not have evidence of TGFBR1*6A acquisition. The highest TGFBR1*6A/TGFBR1 allelic ratio is observed at the tumor's edge, and traces of TGFBR1*6A are detected as far as 2 cm away from the tumor, which is suggestive of centrifugal spread of cells that harbor TGFBR1*6A. Assessment of CDH1 and CDH2 expression does not indicate epithelial-mesenchymal transformation. The results suggest that TGFBR1*6A somatic acquisition is a critical event in the early stages of cancer development that is associated with field cancerization. They also represent the first human report of somatically acquired altered stromal TGF-beta signaling during oncogenesis and the first report of a concordant mutation in the stromal and epithelial compartments in colon cancer.
 ...
PMID:Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. 1789 Feb 72

Human Cripto-1 (CR-1) is a cell membrane protein that is overexpressed in several different types of human carcinomas. In the present study we investigated the mechanisms that regulate the expression of CR-1 gene in cancer cells. We cloned a 2,481 bp 5'-flanking region of the human CR-1 gene into a luciferase reporter vector and transfected NTERA-2 human embryonal carcinoma cells and LS174-T colon cancer cells to test for promoter activity. Activity of CR-1 promoter in both cell lines was modulated by two TGF-beta family members, TGF-beta1 and BMP-4. In particular, TGF-beta1 significantly up-regulated CR-1 promoter activity, whereas a dramatic reduction in CR-1 promoter activity was observed with BMP-4 in NTERA-2 and LS174-T cells. Changes in the CR-1 promoter activity following TGF-beta1 and BMP-4 treatments correlated with changes in CR-1 mRNA and protein expression in NTERA-2 and LS174-T cells. We also identified three Smad binding elements (SBEs) within the CR-1 promoter and point mutation of SBE1 (-2,197/-2,189) significantly reduced response of the CR-1 promoter to both TGF-beta1 and BMP-4 in NTERA-2 and LS174-T cells. Chromatin immunoprecipitation assay also demonstrated binding of Smad-4 to a CR-1 promoter DNA sequence containing SBE1 in LS174-T cells. Finally, BMP-4 inhibited migration of LS174-T cells and F9 mouse embryonal carcinoma cells by downregulation of CR-1 protein. In conclusion, these results suggest a differential modulation of CR-1 gene expression in embryonal and colon cancer cells by two different members of the TGF-beta family.
 ...
PMID:Regulation of human Cripto-1 gene expression by TGF-beta1 and BMP-4 in embryonal and colon cancer cells. 1794 Oct 89

Colon cancer remains a significant global health concern. The impact of specific dietary components on colon tissue likely depends on a host of genomic processes that influence the growth, development, and differentiation of the epithelial cells at the colon crypt surface, where the balance between proliferation and differentiation is maintained possibly through the Wnt (beta-catenin/T-cell factor) signaling pathway. A loss of balance caused by either genetic mutations or environmental factors such as dietary habits can modulate the risk for the formation of aberrant crypt foci and ultimately the development of colon cancer. Evidence exists that butyrate reduces the number and the size of aberrant crypt foci in the colon. Butyrate is a natural histone deacetylase inhibitor as well as a molecule involved with enhanced TGF-beta-induced SMAD3 phosphorylation, increased IFN-gamma-mediated apoptosis, and altered expression of the intestinal muc2 gene that is responsible for mucin synthesis. Other dietary components, such as vitamin D and (n-3) fatty acids, may regulate proliferative properties of colon progenitor cells as well as the differentiation of subcellular lineages. Although these findings are intriguing, there are uncertainties that remain to be resolved including the optimal exposure needed to bring about an effect, the appropriate timing of administration, and if nutrient-nutrient and nutrient-gene interactions determine the overall response. The expanded use of high-throughput technologies, knowledge about the expression of genes and protein fingerprints, and metabolomic profiling will assist in addressing these issues and ultimately in determining the physiological significance of bioactive food components as cancer protectants.
 ...
PMID:Dietary modulation of colon cancer risk. 1795 6

Several studies indicate that cancer-associated fibroblasts play a critical role in cancer cell invasion and metastasis, the hallmarks of malignancy. To better understand the mechanisms underlying such effects, we established a heterotypic model of human fibroblasts (primary colon fibroblasts and immortalized human dermal fibroblasts) in co-culture with human colon cancer cells (HCT-8/E11), using three-dimensional collagen type-I and Matrigel matrices. We report that TGF-beta is the unique and dominant factor to provide pro-invasive signals to HCT-8/E11 colon cancer cells from TGF-beta-treated human fibroblasts in three-dimensional collagen type I and Matrigel matrices. These effects are not mimicked or reversed by EGF or bFGF, and are associated with the TGF-beta-mediated induction of myofibroblast differentiation and functional markers, such as alpha-SMA, the haptotactic matrix molecule TNC, collagen type 1 maturation enzyme P4H, serine protease FAP, and myofibroblast contractility. Accordingly, TGF-beta induced a strong activation of RhoA and stress fiber formation in fibroblasts, with no impact on Rac1-GTP levels. In contrast, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. Taken together, our data imply that TGF-beta and EGF exert invasive growth-promoting actions in human colon tumors through a differential and cumulative impact on the stromal and cancer cell compartments. Our data predict that inhibitors directed at this reciprocal molecular and cellular crosstalk will have therapeutic applications for targeting the invasive growth of human primary tumors and their metastatic spread.
 ...
PMID:Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. 1842 81

Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-beta pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-beta ligand activation, is an epigenetic mechanism for inhibiting the TGF-beta signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-beta signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-beta1 and attenuated TGF-beta signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-beta complex and subsequent TGF-beta receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-beta signaling in colorectal cancer.
 ...
PMID:The aberrant methylation of TSP1 suppresses TGF-beta1 activation in colorectal cancer. 1842 17

Clinical evidence suggests that estradiol replacement therapy reduces colon cancer risk in 'post'menopausal women. In colon epithelial cells, the estrogen receptor beta (ERbeta) is the predominant ER subtype and is thought to mediate the genomic effect of estrogens. The first aim of this study was to investigate the consequence of ERbeta deficiency on intestinal tumorigenesis in the Apc(Min/+) mouse model. Furthermore, to explore the biological mechanisms by which estrogens may influence the pathogenesis of colorectal cancer, we performed gene expression profiles in colonocytes from ovariectomized wild-type (WT) vs. ERbeta(-/-) mice, treated with estradiol (E(2)) or vehicle. Specifically in female, ERbeta deficiency was found to be associated with higher adenoma multiplicity in the small intestine, but not in the colon. Furthermore, tumors from ERbeta(-/-)Apc(Min/+) female mice were on average significantly larger than those from control Apc(Min/+) mice. Higher steady-state proliferation in epithelial cells of the jejunum and colon from ERbeta(-/-)Apc(Min/+) vs. Apc(Min/+) female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGFbeta signaling pathway to be modulated in colonocytes, especially for the WT + E(2) vs. WT + Vehicle and the ERbeta(-/-) + E(2) vs. WT + E(2) comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGFbeta pathway to be upregulated in colonocytes from E(2)-treated WT and ERbeta(-/-) mice and downregulated in ERbeta-deficient mice, mostly in an E(2)-independent manner. Therefore, our results demonstrate that ERbeta deficiency enhances small intestinal tumorigenesis and suggest that modulation of the TGFbeta signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis.
 ...
PMID:Estrogen receptor beta deficiency enhances small intestinal tumorigenesis in ApcMin/+ mice. 1846 59


<< Previous 1 2 3 4 5 6 7 Next >>