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

We have previously reported that Sp3 acts as a transcriptional repressor of transforming growth factor-beta receptors type I (RI) and type II (RII). We now present data suggesting that treatment of MCF-7L breast and GEO colon cancer cells with 5-aza cytidine (5-azaC) leads to down-regulation of Sp3 and the concomitant induction of RI and RII. Western blot and gel shift analyses on 5-azaC-treated MCF-7L and GEO nuclear extracts indicated reduced Sp3 protein levels and decreased binding of Sp3 protein to radiolabeled consensus Sp1 oligonucleotide. Southwestern analysis detected decreased binding of Sp3 to RI and RII promoters in 5-azaC-treated MCF-7L and GEO cells, suggesting a correlation between decreased Sp3 binding and enhanced RI and RII expression in these cells. Reverse transcription-polymerase chain reaction and nuclear run-on data from 5-azaC-treated MCF-7L and GEO cells indicated down-regulation of Sp3 mRNA as a result of decreased transcription of Sp3. We reported earlier that 5-azaC treatment induces RI and RII expression through increased Sp1 protein levels/activities in these cells. These studies demonstrate that the effect of 5-azaC involves a combination of effects on Sp1 and Sp3.
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PMID:5-azaC treatment enhances expression of transforming growth factor-beta receptors through down-regulation of Sp3. 1144 24

Some previous studies have reported an improved prognosis in sporadic colon cancers with microsatellite instability, whereas others have not. In addition, relatively few of those reporting an improved prognosis controlled for tumor stage or were population-based. Therefore, we evaluated the relationship between microsatellite instability and prognosis, tumor stage, and other clinical variables in a population-based study of 1026 individuals. Microsatellite instability was determined by the noncoding mononucleotide repeat BAT-26 and the coding mononucleotide repeat in transforming growth factor-beta receptor type II. Significant relationships were seen between microsatellite instability and proximal tumor location, female gender, young and old age at diagnosis, poor histological differentiation, and low tumor stage (P < 0.01). There was a significant relationship between microsatellite instability and improved prognosis, even after adjusting for stage, with a reduction in the risk of death attributable to colon cancer of approximately 60%. Most of this risk reduction occurred in individuals with American Joint Committee on Cancer stage III tumors, although transforming growth factor-beta receptor type II mutations were associated with a significant reduction in colon cancer death in tumors with distant metastases. We conclude that microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.
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PMID:Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. 1201 Aug 67

Rectal administration of trinitrobenzene sulfonic acid (TNBS) produces chronic colitis in experimental animals. However, the role of epithelial cellular protein(s) in this model is unknown. We examined whether oral tolerance can be induced in this model with colon epithelial cell proteins and whether it is organ specific. Rats were fed five times with extracts of LS-180 human colon cancer cells or HT 1080 human fibroblast cells. Syngeneic normal rat colon or small intestinal extracts were fed to separate groups of rats. After oral feedings, each rat received TNBS by enema. Rats were killed 15 days later, and the following were measured: gross and histologic disease score, weight, thickness, and myeloperoxidase values of colon and serum interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels. Rectal TNBS alone produced severe colitis with a 26% mortality rate. Rats fed LS-180 or rat colon extract before TNBS enema were protected, as evidenced by reductions in mortality rate, disease scores, and myeloperoxidase values. However, rats fed HT 1080 or small intestine extract lacked such protection. To examine the possible mechanism of the oral tolerance, T lymphocytes from mesenteric lymph nodes and spleen of LS-180 extract-fed rats were passively transferred to naive rats, and this was followed by TNBS enema. These rats showed clear protection. Protected animals had low IFN-gamma and high TGF-beta levels. This study demonstrates that cellular protein(s) from human colon epithelial cells, but not from human fibroblasts, can induce oral tolerance in experimental colitis. This oral tolerance is mediated by primed mesenteric and splenic T lymphocytes.
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PMID:Colon epithelial cellular protein induces oral tolerance in the experimental model of colitis by trinitrobenzene sulfonic acid. 1157 20

Somatic cell gene targeting was used to create an isogenic set of human colon cancer cells that differs only in the presence or absence of their endogenous activated beta-catenin oncogene. Affymetrix Genechip expression profiling of parental cells and gene-targeted derivatives identified numerous novel genes whose expression was dependent on the presence of oncogenic beta-catenin. The transforming growth factor-beta family member bone morphogenetic protein 4 (BMP4), whose receptor is mutated in a rare inherited gastrointestinal cancer predisposition syndrome, was the most highly differentially expressed gene. Additional experiments revealed that the oncogenic allele of beta-catenin specifically is absolutely required for BMP4 expression and secretion by human cancer cells and that BMP4 is overexpressed and secreted by human colon cancer cells with mutant adenomatous polyposis coli genes. These data identify the presence of regulatory interactions between the Wnt and BMP signaling pathways in cancer pathogenesis, providing an intriguing connection between the sporadic and inherited forms of a common human malignancy.
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PMID:Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells. 1201 47

Microsatellite instability in sporadic colon cancer is associated with an improved prognosis. Recent studies, however, have suggested that microsatellite unstable cancers with mutations in the proapoptotic gene BAX have a relatively poor prognosis, whereas those with mutations in transforming growth factor-beta receptor type II (TGFBRII) have a relatively good prognosis. Using instability in the non-coding mononucleotide repeat BAT-26 as a measure of generalized microsatellite instability, we evaluated the prognosis of unstable colon cancers with and without frameshift mutations in the coding mononucleotide repeats of BAX and TGFBRII in a population-based sample of 1,427 individuals. BAX mutations were identified in 39.0% (64/164) of unstable colon cancers, whereas TGFBRII mutations were identified in 79.3% (138/174) of unstable colon cancers. Unstable colon cancers with and without instability in BAX and TGFBRII were associated with very similar and statistically indistinguishable percentage 5-year survivals and Kaplan-Meier survival curves; stable colon cancers were associated with a significantly worse 5-year survival and Kaplan-Meier survival (P < 0.001 and P < 0.013, respectively, compared against BAT-26 unstable). The age- and stage-adjusted risk of death associated with BAX or TGFBRII mutations was not significantly different from that of unstable tumors without such mutations. We conclude that instability-induced mutations in BAX or TGFBRII do not have a significant impact on the good prognosis of colon cancers with microsatellite instability.
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PMID:Prognostic implications of BAX and TGFBRII mutations in colon cancers with microsatellite instability. 1237 32

Smad4 is a tumor suppressor gene that is commonly lost or mutated in colorectal and pancreatic cancers. The activated transforming growth factor-beta (TGF-beta) receptor phosphorylates Smad2 and Smad3, which then complex with Smad4 and translocate to the nucleus. Smad4 mutations when detected as present in some human cancers have been considered sufficient to inactivate TGF-beta signaling. In this work, we describe a colon cancer cell line, VACO-9M, that is Smad4 null when analysed by multiple assays. To study the role of Smad4 in TGF-beta-induced translocation of the receptor-activated Smads to the nucleus, we analysed by immunofluorescence the cellular localization of endogenous Smad2 and Smad3 after TGF-beta treatment of VACO-9M, plus four additional Smad4 null cell lines of breast (MDA-MB-468), or pancreatic (BxPC3, Hs766T, CFPAC-1) origin. In each cell line, TGF-beta treatment resulted in both Smad2 and Smad3 moving to the nucleus in a Smad4-independent fashion. Nuclear translocation of Smad2 and Smad3 was, however, not sufficient to activate reporters for TGF-beta-induced transcriptional responses, which were however restored by transient transfection of wild-type Smad4. We conclude that Smad4 is not required for nuclear translocation of Smad2 and Smad3, but is needed for activation of at least certain transcriptional responses.
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PMID:TGF-beta-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines. 1261 56

The p53 tumor suppressor protein plays a key function in the cellular response to stress by activating a subset of genes responsible for cell cycle arrest and apoptosis. Activation of the p53 pathway in tumor cells has been proposed as a novel approach to cancer therapy and substantial efforts have been dedicated to the discovery of pharmacological p53 activators. Here, we show that the transforming growth factor-beta superfamily cytokine, macrophage inhibitory cytokine-1 (MIC-1), can serve as a secreted biomarker for activation of p53 in both cellular and xenograft models of human cancer. Using doxorubicin treatment in the HCT116 colon cancer cell line, we have shown that MIC-1 secretion into culture media is correlated with p53 pathway activation as measured by the up-regulation of its downstream transcriptional target p21. When transplanted into nude mice, HCT116 cells continued to secret human MIC-1 and mouse plasma levels correlated well with tumor volume. Treatment of these animals with a single dose of doxorubicin led to activation of the p53 pathway and a nearly 4-fold elevation of the plasma MIC-1 level, which was paralleled by p21 induction in the tumor xenografts. Estimation of MIC-1 concentration, both in vivo and in vitro, represents a novel tool for the study of p53 pathway and development of p53-activating therapeutics.
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PMID:Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. 1457 67

Invasion of stromal host cells, such as myofibroblasts, into the epithelial cancer compartment may precede epithelial cancer invasion into the stroma. We investigated how colon cancer-derived myofibroblasts invade extracellular matrices in vitro in the presence of colon cancer cells. Myofibroblast spheroids invade collagen type I in a stellate pattern to form a dendritic network of extensions upon co-culture with HCT-8/E11 colon cancer cells. Single myofibroblasts also invade Matrigel trade mark when stimulated by HCT-8/E11 colon cancer cells. The confrontation of cancer cells with extracellular matrices and myofibroblasts, showed that cancer-cell-derived transforming growth factor-beta (TGF-beta) is required and sufficient for invasion of myofibroblasts. In myofibroblasts, N-cadherin expressed at the tips of filopodia is upregulated by TGF-beta. Functional N-cadherin activity is implicated in TGF-beta stimulated invasion as evidenced by the neutralizing anti-N-cadherin monoclonal antibody (GC-4 mAb), and specific N-cadherin knock-down by short interference RNA (siRNA). TGF-beta1 stimulates Jun N-terminal kinase (also known as stress-activated protein kinase) (JNK) activity in myofibroblasts. Pharmacological inhibition of JNK alleviates TGF-beta stimulated invasion, N-cadherin expression and wound healing migration. Neutralization of N-cadherin activity by the GC-4 or by a 10-mer N-cadherin peptide or by siRNA reduces directional migration, filopodia formation, polarization and Golgi-complex reorientation during wound healing. Taken together, our study identifies a new mechanism in which cancer cells contribute to the coordination of invasion of stromal myofibroblasts.
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PMID:Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding. 1533 29

Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.
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PMID:Transforming growth factor-beta suppresses nonmetastatic colon cancer through Smad4 and adaptor protein ELF at an early stage of tumorigenesis. 1589 14

Some markers of angiogenic endothelial cells are emerging as targets of cancer therapy. The present study compares the expression of CD105 with that of other endothelial markers in all tissue layers during the development of colon cancer. We immunohistochemically analyzed the expression of the colon adenoma-carcinoma sequence by endothelial cells using a panel of eight endothelial markers. We examined sections from endoscopic mucosal resection and surgical resection of tubular adenoma (n=31), carcinoma in adenoma (n=11), and adenocarcinoma (n=34). Cylindrical cores were punched out from donor paraffin blocks of normal mucosa adjacent to tumors, from tumor lesions of mucosa, submucosa, muscularis propria, subserosa, and serosa, and from lymph node metastases. CD31 (PECAM-1) was universally expressed in the blood vessels of adenoma-carcinoma lesions as well as in normal mucosal vessels (80-95%), with no significant differences. In contrast, cancer-associated blood vessels (up to 80%) and cancer cells themselves expressed high levels of CD105. In normal mucosa, CD105 was weakly expressed in endothelial cells of capillaries (< or =21%), and significant differences in its expression in endothelial cells between the normal mucosa and adenoma, carcinoma in adenoma, and adenocarcinoma were found. Flt-1, Flk-1, transforming growth factor-beta1, transforming growth factor-beta receptor II, and CD44 were strongly expressed in the cancer cells but were not expressed in the blood vessels. Vascular endothelial growth factor was expressed at <30% in the blood vessels of adenoma, carcinoma in adenoma, and carcinoma. Moreover, this study provided evidence that CD105 was expressed exclusively in endothelial blood vessels by double immunostaining of CD105 and D2-40. The present study shows that de novo blood vessels of colon cancer specifically express CD105. These findings provide the basis for novel antiangiogenic cancer therapies.
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PMID:Endoglin (CD105) expression in angiogenesis of colon cancer: analysis using tissue microarrays and comparison with other endothelial markers. 1617 81


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