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

Inflammatory bowel diseases (IBD) are linked to an increased risk of developing colon cancer, by inflammatory mediators and alterations to the extracellular matrix (ECM). The events induced by inflammatory mediators lead to dysregulated activation and induction of inflammatory genes such as cyclooxygenase-2 (COX-2). COX-2 is involved in the conversion of arachidonic acid to biologically active prostanoids and is highly upregulated in colon cancer. Since inflammation-induced changes to the extracellular matrix could affect integrin activities, we here investigated the effect of integrin signalling on the level of COX-2 expression in the non-transformed intestinal epithelial cell lines, Int 407 and IEC-6. Adhesion of these cells to a collagen I- or IV-coated surface, increased surface expression of alpha2beta1 integrin. Activation of integrins with collagen caused an increased cox-2 promoter activity, with a subsequent increase in COX-2 expression. The signalling cascade leading to this increased expression and promoter activity of cox-2, involves PKCalpha, the small GTPase Ras and NFkappaB but not Erk1/2 or Src activity. The integrin-induced increase in cellular COX-2 activity is responsible for an elevated generation of reactive oxygen species (ROS) and increased cell migration. This signalling pathway suggests a mechanism whereby inflammation-induced modulations of the ECM, can promote cancer transformation in the intestinal epithelial cells.
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PMID:Alpha2beta1 integrin signalling enhances cyclooxygenase-2 expression in intestinal epithelial cells. 1697 45

Obesity, a risk factor for colon cancer, is associated with elevated serum levels of leptin, a protein produced by adipocytes. The aim of the present study was to clarify the effects of adipose tissue on colon cancer proliferation by using cultured cell lines. To achieve this, colon cancer cells (CACO-2, T84, and HT29) were cocultured with adipose tissue, isolated mature adipocytes, and isolated preadipocytes in a three-dimensional collagen gel culture system. The adipocytes and preadipocytes used were isolated from C57BL/6J and leptin-deficient ob/ob mice. Proliferation of the cancer cells was evaluated by nuclear bromodeoxyuridine uptake. The adipose tissue, mature adipocytes, and preadipocytes isolated from C57BL/6J mice significantly increased the proliferation of the colon cancer cells. This trophic effect of mature adipocytes on the cancer cell lines was observed only for cells from lean littermates and not for those from ob/ob mice. In contrast, the trophic effect of preadipocytes was not abolished in ob/ob mice, and this finding was supported by the result that leptin had a trophic effect on cancer cells. In conclusion, adipocytes were able to enhance the proliferation of colon cancer cells in vitro, partly via leptin, suggesting that adipose tissues, including mature adipocytes and preadipocytes, may promote the growth of colorectal cancer.
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PMID:Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. 1717 30

Gardner fibroma (GAF) is a benign soft tissue lesion with a predilection for childhood and adolescence and an association with familial adenomatous polyposis (FAP) and desmoid type fibromatosis (desmoid). We report 45 patients with GAF with clinicopathologic correlation and immunohistochemical analysis for beta-catenin and related proteins. Forty-five patients with 57 GAFs were identified from surgical pathology and consultation files. Immunohistochemistry for beta-catenin, cyclin-D1, and C-myc was performed on formalin-fixed, paraffin-embedded tissues using standard techniques in 25 GAFs from 24 patients. Information about family history, intestinal polyps, colon cancer, and soft tissue tumors was available in 23 patients. Sixty-nine percent had known FAP or adenomatous polyposis coli (APC), 22% had no history of familial polyps or soft tissue tumors, and 13% had an individual or family history of soft tissue masses and/or desmoids, with follow-up periods of 6 months to 26 years (median 3 y, mean 5 y). The age range at initial diagnosis was 2 months to 36 years. Seventy-eight percent were diagnosed in the first decade, 15% in the second decade, and 7% in the third decade. Eight patients (18%) had documented desmoids concurrently or later; 4 of these had FAP and 1 had familial desmoids. Sites of GAF included the back and paraspinal region in 61%, the head and neck in 14%, the extremities in 14%, and the chest and abdomen in 11%. All displayed a bland hypocellular proliferation of haphazardly arranged coarse collagen fibers with a bland hypocellular proliferation of inconspicuous spindle cells, small blood vessels, and a sparse mast cell infiltrate. Immunohistochemically, 64% showed nuclear reactivity for beta-catenin (9 patients with known APC, 5 without definite information about FAP). One hundred percent showed nuclear reactivity for both cyclin-D1 and C-myc. beta-catenin reactivity had no correlation with age, site, or recurrence. Two beta-catenin-negative GAFs were from FAP patients. In conclusion, GAF has a predilection for childhood and early adulthood, a strong association with FAP/APC, an association with concurrent or subsequent development of desmoids, and overexpression of beta-catenin and other proteins in the APC and Wnt pathways. The proportion of sporadic GAFs that have APC mutation remains to be determined.
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PMID:Gardner fibroma: a clinicopathologic and immunohistochemical analysis of 45 patients with 57 fibromas. 1732 83

Matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are involved in colon cancer progression and metastasis due to their ability to degrade extracellular matrix (ECM) components. In previous studies we described the MMP-9 hemopexin like domain (MMP-9-PEX) as an MMP-9 antagonist. In the present study it was examined whether recombinant MMP-9-PEX has an inhibitory effect on migration and adhesion of colorectal carcinoma cells. Furthermore, we searched for MMP-9 substrate binding sites within the MMP-9-PEX by surface plasmon resonance. Migration of SW620 and LS174 cells was investigated in a modified Boyden chamber assay. In the presence of 0.2 microg/ml MMP-9-PEX migration of SW620 was decreased by 34%, while addition of 0.4 microg/ml diminished migration by 56%. Migration of LS174 cells was not affected by MMP-9-PEX. Adhesion studies were performed on 96-well plates coated with gelatin, collagen type I, and laminin, respectively. In the presence of MMP-9-PEX, adhesion of SW620 cells to these coating substrates was significantly inhibited. Surface plasmon resonance studies revealed binding of collagen type I and IV, elastin, and fibrinogen to proMMP-9 as well as to MMP-9-PEX. However, equilibrium constants (Kd) indicated a higher affinity of proMMP-9 to the matrix proteins. This could indicate that there is more than one binding site for matrix components within the entire proMMP-9 molecule. Since migration and adhesion of metastatic colorectal carcinoma cells were reduced by MMP-9-PEX, this recombinant MMP-9 antagonist might be of therapeutical interest.
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PMID:MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cells. 1733 39

Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.
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PMID:Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. 1733 89

Increasing evidence is emerging highlighting the role of parathyroid hormone-related protein (PTHrP) during metastasis by regulating cell adhesion. The current study demonstrated that modulation of PTHrP expression by PTHrP overexpression and small interfering RNA-induced silencing resulted in changes in cell adhesion and integrin expression. RNA interference of endogenous PTHrP caused a significant reduction in cell adhesion of a breast cancer cell line to collagen type I, fibronectin and laminin (P<0.05) and of a colon cancer cell to collagen type I and fibronectin (P<0.05). Overexpression of PTHrP induced a significant increase in cell adhesion of colon (P<0.0001) and breast (P<0.05) cancer cells to the same extracellular matrix proteins. These PTHrP-mediated effects were attributed to changes in integrin expression as the differences in adhesion profile correlated with the integrin expression profile. In an attempt to elucidate the mechanism whereby PTHrP regulates integrin expression, promoter activity of the integrin alpha5 subunit was analysed and significant increases in transcriptional activity were observed in PTHrP overexpressing cells (P<0.0001), which was dependent on nuclear localisation. These results indicate that modulation of cell adhesion is a normal physiological action of PTHrP, mediated by increasing integrin gene transcription.
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PMID:PTHrP increases transcriptional activity of the integrin subunit alpha5. 1740 57

Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer.
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PMID:Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. 1740 37

Optical coherence tomography (OCT) and laser-induced fluorescence (LIF) spectroscopy each have clinical potential in identifying human gastrointestinal (GI) pathologies, yet their diagnostic capability in mouse models is unknown. In this study, we combined the 2 modalities to survey the GI tract of a variety of mouse strains and ages and to sample dysplasias and inflammatory bowel disease (IBD) of the intestines. Segments (length, 2.5 cm) of duodenum and lower colon and the entire esophagus were imaged ex-vivo with combined OCT and LIE We evaluated 30 normal mice (A/J and 10- and 21-wk-old and retired breeder C57BL/6J) and 10 mice each of 2 strains modeling colon cancer and IBD (Apc(Min) and IL2-deficient mice, respectively). Histology was used to classify tissue regions as normal, Peyer patch, dysplasia, adenoma, or IBD. Features in corresponding OCT images were analyzed. Spectra from each category were averaged and compared via Student t tests. OCT provided structural information that led to identification of the imaging characteristics of healthy mouse GI. With histology as the 'gold standard,' we developed preliminary image criteria for early disease in the form of adenomas, dysplasias, and IBD. LIF characterized the endogenous fluorescence of mouse GI tract, with spectral features corresponding to collagen, NADH, and hemoglobin. In the IBD sample, LIF emission spectra displayed potentially diagnostic peaks at 635 and 670 nm, which we attributed to increased porphyrin production by bacteria associated with IBD. OCT and LIF appear to be useful and complementary modalities for ex vivo imaging of mouse GI tissues.
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PMID:Ex vivo optical coherence tomography and laser-induced fluorescence spectroscopy imaging of murine gastrointestinal tract. 1753 18

Actin depolymerizing factor (ADF)/cofilin family proteins are key regulators of actin filament turnover and cytoskeleton reorganization. The role of cofilin-1 in cell motility has been demonstrated in several cell types but remained poorly documented in the case of colon cancer. In addition, the putative function of destrin (also known as ADF) had not been explored in this context despite the fact that it is expressed in all colon cancer cell lines examined. We were therefore prompted to evaluate the respective contributions of these proteins to the invasive properties of the human colon cancer Isreco1 cell line, which expresses a comparatively high destrin/cofilin ratio. Reduction of cofilin-1 or destrin expression in Isreco1 cells using RNA interference led to an increase of the number of multinucleated cells and altered polarized lamellipodium protrusion and distribution of paxillin-containing adhesions. Both cofilin-1 and destrin silencing enhanced cell adhesion to extracellular matrix components. However, only destrin appeared to be required for cell migration on collagen I and for cell invasion through Matrigel in response to the proinvasive neuroendocrine peptide bombesin. This differential functional involvement was supported by a destrin-dependent, cofilin-independent phosphorylation of p130Crk-associated substrate (p130Cas) upon cell adhesion to collagen I or Matrigel. Taken together, our results suggest that destrin is a significant regulator of various processes important for invasive phenotype of human colon cancer Isreco1 cells whereas cofilin-1 may be involved in only a subset of them.
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PMID:Differential involvement of destrin and cofilin-1 in the control of invasive properties of Isreco1 human colon cancer cells. 1758 72

Vimentin is a type III Intermediate filament protein that is expressed frequently in epithelial carcinomas correlating with invasiveness and poor prognosis. We have analysed migration and adhesion to collagenous matrix of a panel of carcinoma cell lines. In vitro invasiveness was highest in vimentin-positive SW480 colon cancer and MDA-MB-231 breast cancer cells and the role of vimentin in these cell lines was investigated by RNA interference. Down-regulation of vimentin expression resulted in impaired migration in both scratch-wound experiments and in invasion assays through cell culture inserts coated with collagen gel. Compromised migration was observed in both cell lines, whereas cell attachment assays revealed impaired adhesion to fibrillar collagen in MDA-MB-231 cells while the adhesion of vimentin-ablated SW480 cells, that express both vimentin and keratin intermediate filaments was not affected. In conclusion, ablation of vimentin expression inhibits migration and invasion of colon and breast cancer cell lines.
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PMID:Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. 1758 78


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