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

The mechanisms by which growth factors cooperate with cell adhesion molecules to modulate epithelial cell motility remain poorly understood. Here, we investigated the role of the E-cadherin/catenin complex in insulin-like growth factor (IGF-I)-dependent cell migration and invasion. We used variants of the HCT-8 colon cancer family that differ in their expression of alphaE-catenin, an intracellular molecule that links the E-cadherin/catenin complex to the actin cytoskeleton. Migration was determined using a monolayer wound model and cell invasion by the penetration of the cells into type-I collagen gels. We showed that alpha-catenin-deficient cells were not able to migrate in cohort upon IGF-I stimulation. Transfection of these cells with alpha-catenin isoforms (alphaN- or alphaT-catenin) restored migratory response IGF-I. These results suggest that alpha-catenins are involved in the signal issued from the E-cadherin/catenin complex to regulate IGF-I-stimulated migration. In contrast, IGF-I promoted invasion of both alpha-catenin-deficient and alpha-catenin-expressing cells, indicating that alpha-catenin did not participate in the regulation of IGF-I-induced invasion. Inhibition of E-cadherin function by treatment with MB-2 monoclonal antibodies inhibited both IGF-I-dependent cell migration and invasion. Taken together, our results indicate that functional alpha-catenin is essential for migration but not for invasion, while E-cadherin is involved in both phenomena.
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PMID:Alpha-catenin is required for IGF-I-induced cellular migration but not invasion in human colonic cancer cells. 1496 Oct 74

Mutations in APC or in beta-catenin, which are common in colon cancer, lead to constitutive activation of beta-catenin/Tcf-dependent signaling. alpha-Catenin is also found in some colon cancer cell nuclei, and loss of its expression correlates with increased beta-catenin/Tcf transcriptional activity. Moreover, targeted expression of alpha-catenin in the nucleus inhibits beta-catenin/Tcf-dependent transcription. Thus, an understanding of the regulation of alpha-catenin localization could provide insight into the control of beta-catenin signaling. While the beta-catenin/Tcf complex can promote nuclear import of alpha-catenin, the mechanism for its nuclear export is not known. We found that leptomycin B (LMB) inhibited nuclear export of GFP-alpha-catenin in HCT116 colon cancer cells, suggesting that alpha-catenin localization is regulated by CRM-1-dependent nuclear export. We identified two putative nuclear export signals in a domain of alpha-catenin that overlaps with the beta-catenin binding domain. Using a nuclear export assay, we determined that one of these (NES1) is a weak LMB-insensitive NES, whereas the other (NES2) is strong and LMB-sensitive. Mutations in either NES reduced nuclear export of alpha-catenin in HCT116 cells. In addition, mutations in NES1, but not NES2, reduced binding of alpha-catenin to beta-catenin and impaired the ability of alpha-catenin to repress beta-catenin/Tcf-dependent transcription. Therefore, NES1 is required both for repression of beta-catenin signaling and for nuclear export, while NES2 is required only for nuclear export.
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PMID:Nuclear export of alpha-catenin: overlap between nuclear export signal sequences and the beta-catenin binding site. 1505 98

Alterations in adhesion molecules, angiogenesis, and matrix metalloproteinases have been associated with metastasis and intravasation. The present study investigated the role of these metastatic factors in the context of primary colorectal tumor. Intravasated colorectal epithelial cells were detected by an RT-PCR assay, and the expression of E-cadherin, alpha-catenin, or beta-catenin as well as the vascularity of tumor were assessed by immunohistochemical staining. Activity of matrix metalloproteinase was assessed by gelatin zymography. The tumor venous blood was positive for guanylyl cyclase C (GCC) mRNA expression in 40 of 68 patients, but alteration in expression of E-cadherin, alpha-catenin, or beta-catenin was not significantly associated with the presence of colorectal epithelial cells in paired portal venous blood. Further, matrix metalloproteinase activity did not correlate with the presence of intravasated colorectal epithelial cells. Multivariate analysis demonstrated that the only factor associated with intravasated colorectal tumor cells was the vascularity of the tumor. Thus, metastasis of colon cancer may result from passive entry into the circulation secondary to angiogenic factors and does not appear to involve other metastatic factors studied in our experiments.
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PMID:Intravasation-related metastatic factors in colorectal cancer. 1519 12

Various authors have reported reduced synthesis of epithelial junctional proteins during dedifferentiation, tumorigenesis and metastasis in a great variety of tumors. Consequently, it is generally accepted that loss of adhesive molecules and adhesion structures is implicated in the development of an invasive phenotype and poor patient prognosis. Colon carcinomas, on the other hand, were shown to behave differently as synthesis of main adhesive proteins continues despite the development of an invasive phenotype. In this study we used cultured cells grown under conditions that inhibited intercellular adhesion (low Ca2+ concentration) and compared these results with data obtained from metastasizing colon cancer cells (signet ring cell carcinoma). Characterization of these proteins and their structures were performed by immunoprecipitations, Western blot analysis, immunohistochemistry, pre-embedding immuno-electron microscopy, and a new method to perform immuno-electron microscopy on paraffin-embedded material, which we present in this paper. We demonstrate that synthesis carries on for both, the desmosomal and the proteins of the zonula adhaerens. While, however, the assembly of desmosomal structures in the form of half-desmosomes at the cell surface continues, those of the zonula adhaerens did not. Instead E-cadherin was found, although associated with alpha-catenin, beta-catenin, and plakoglobin, evenly distributed at the plasma membrane of the cultured cells and also at the surface of the dissociated tumor cells. We conclude from our observations that continued expression and synthesis of junctional proteins do not necessarily contribute to the suppression of tumor invasion and metastasis of colon cancer.
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PMID:Synthesis of junctional proteins in metastasizing colon cancer cells. 1581 18

Dynamic crosstalk between cell adhesion molecules, extracellular matrix and soluble informative factors is essential for cancer cell migration and invasion. Here, we investigated the mechanisms by which the E-cadherin/catenin complex and alpha v integrin can modulate insulin-like growth factor-I (IGF-I)-induced cell migration. Human colon mucosa, human colon cancer cell lines, HT29-D4 and HCT-8 derivatives that differ in their expression of alpha-catenin, were used as models. Interactions between E-cadherin, alpha v integrin and IGF-I receptor (IGF-IR) were analyzed by coimmunoprecipitation and immunolocalization experiments. The impact of these interactions on cell mobility was determined by haptotaxis assays. We report that alpha v integrin, E-cadherin and IGF-IR form a ternary complex in both cultured cancer cells and human normal colonic mucosa. alpha-Catenin regulates the scaffolding of this complex. IGF-IR ligation by IGF-I induces the disruption of the complex and the relocalization of alpha v integrin from cell-cell contacts to focal contact sites. This perturbation is correlated with the observed increase in cell migration. These results suggest that regulation of the alpha v integrin/E-cadherin/IGF-IR scaffolding is essential for the modulation of cell mobility. Its alteration could be of major importance to sustain alterations in cell adhesion that occur during cancer cell invasion and metastasis.
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PMID:Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. 1795 85

IQGAP1 is a multifunctional protein involved in actin cytoskeleton assembly and E-cadherin-mediated cell adhesion. We reported previously IQGAP1 overexpression in human colorectal carcinomas especially at the invasion front (IF) and that such overexpression tended to correlate with lymph node metastasis in advanced cases. Thus, in this study, we investigated the clinicopathological significance of IQGAP1 expression in 85 cases of pT2-3 colorectal carcinomas with special reference to its expression pattern and prognosis, followed by analysis of the role of IQGAP1 in cancer invasion in vitro. Quantitative reverse transcription-PCR showed significant upregulation of IQGAP1 in colorectal carcinomas compared with normal mucosa. Immunohistochemically, IQGAP1 expression pattern was classified into diffuse (20%), IF-associated (35.3%) and focal (44.7%). The diffuse pattern was associated with higher rates of distant metastasis. Patients with IQGAP1 overexpression and diffuse pattern had significantly shorter survival (p < 0.0001) than others, and the diffuse pattern was an independent predictor of poor survival by multivariate analysis. In vitro invasion assays using three human colon carcinoma cell lines showed that IQGAP1 siRNA significantly suppressed hepatocyte growth factor (HGF)-stimulated cell invasion. HGF reduced membranous localization of alpha-catenin, but did not alter localization of E-cadherin, beta-catenin and IQGAP1 in membranes. Suppression of IQGAP1 expression by siRNA did not alter membranous localization of alpha-catenin even in the presence of HGF. Our results indicate that IQGAP1 plays a critical role in colon cancer cell invasion, and therefore diffuse and high expression of IQGAP1 predicts poor prognosis in patients with colorectal carcinoma.
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PMID:Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion. 1985 15


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