The role of adhesion molecules, αvβ3, αvβ5 and their ligands in the tumor cell and endothelial cell adhesion
Institute of Basic Medical Sciences, Peking Union Medical College, Beijing, PR China. European Journal of Cancer Prevention
(Impact Factor: 3.03).
01/2008; 16(6):517-27. DOI: 10.1097/CEJ.0b013e3280145c00
Tumor metastasis is a complex process involving the interaction between tumor cells and endothelial cells in which some adhesion molecules play an important role. It was our aim to investigate the role of the adhesion molecules, alpha v beta 3 and alpha v beta 5 and their ligands, developmental endothelial locus-1 (Del-1) and L1, in tumor cell adhesion to endothelial cells in vitro. In this study, the expression and regulation of alpha v beta 3, alpha v beta 5 and intercellular adhesion molecule -1 on liver sinusoidal endothelial cells and liver cancer endothelial cells (T3A) were analyzed by real-time PCR and fluorescent-activated cell sorter. The expression and regulation of the integrin ligands, Del-1 and L1, in six tumor cell lines were analyzed by real-time PCR and western blot. We found the expressions of alpha v beta 3 and alpha v beta 5 were higher on T3A than that on liver sinusoidal endothelial cells, whereas expression of intercellular adhesion molecule-1 was lower on T3A than that on liver sinusoidal endothelial cells. After 24 h hypoxia, the expressions of alpha v beta 3 and alpha v beta 5 were upregulated on T3A and liver sinusoidal endothelial cells; the expression of intercellular adhesion molecule-1 was increased on liver sinusoidal endothelial cells, but remained unchanged on T3A. Del-1 and L1 expression levels were obviously diverse in various tumor cell lines and differentially modulated after 12 h hypoxia. The adhesion of tumor cells with Del-1 and L1 expression was higher in T3A than that in liver sinusoidal endothelial cells, and was significantly increased under hypoxic conditions. Interestingly, the tumor cell adherence could be inhibited by antibodies against alpha v beta 5 and alpha v beta 5, but not by an antibody against intercellular adhesion molecule-1. The adhesion of tumor cells without Del-1 and L1 expression was also higher on T3A than that on liver sinusoidal endothelial cells, but the adhesion could not be inhibited by antibodies against alpha v beta 5, alpha v beta 5 or intercellular adhesion molecule-1, suggesting that other receptors are involved. In conclusion, alpha v beta 5, alpha v beta 5 and their ligands Del-1 and L1 play an important role in the process of tumor cells moving from the original place.
Available from: wu Yong
- "Invasion and metastasis are important biological characteristics of malignant tumors. Metastatic formation requires specific cell-to-cell and cell-to-extracellular matrix (ECM) interactions mediated by integrins , cadherins , selectins , etc. In particular, integrin-mediated adhesion of tumor cells to ECM proteins and cell surface components is considered a crucial event in metastasis. "
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ABSTRACT: Fibronectin (FN) is known to be a large multifunction glycoprotein with binding sites for many substances, including N-terminal and C-terminal heparin-binding domains. We investigated the effects of highly purified rhFNHN29 and rhFNHC36 polypeptides originally cloned from the two heparin-binding domains on the adhesion and invasion of highly metastatic human hepatocellular carcinoma cells (MHCC97H) and analyzed the underlying mechanism involved.
The MHCC97H cells that adhered to FN in the presence of various concentrations of rhFNHN29 and rhFNHC36 polypeptides were stained with crystal violet and measured, and the effects of rhFNHN29 and rhFNHC36 on the invasion of the MHCC97H cells were then detected using the Matrigel invasion assay as well as a lung-metastasis mouse model. The expression level of integrins and focal adhesion kinase (FAK) phosphotyrosyl protein was examined by Western blot, and the activity of matrix metalloproteinases (MMPs) and activator protein 1 (AP-1) was analyzed by gelatin zymography and the electrophoretic mobility band-shift assay (EMSA), respectively.
Both of the polypeptides rhFNHN29 and rhFNHC36 inhibited adhesion and invasion of MHCC97H cells; however, rhFNHC36 exhibited inhibition at a lower dose than rhFNHN29. These inhibitory effects were mediated by integrin αvβ3 and reversed by a protein tyrosine phosphatase inhibitor. Polypeptides rhFNHN29 and rhFNHC36 abrogated the tyrosine phosphorylation of focal adhesion kinase (p-FAK) and activation of activator protein 1 (AP-1), resulting in the decrease of integrin αv, β3 and β1 expression as well as the reduction of MMP-9 activity.
Polypeptides rhFNHN29 and rhFNHC36 could potentially be applicable to human liver cancer as anti-adhesive and anti-invasive agents.
Available from: PubMed Central
- "The present study shows here that the human colon cancer LS-174T and HT29 cells expressed Del1. The difference in Del1 expression may be cell type-dependent, as previously reported that the Del1 expression was obviously diverse in various tumor cells [6,8]. "
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ABSTRACT: Developmentally regulated endothelial cell locus-1 (Del1) is an embryonic angiogenic factor expressed in early embryonic endothelial cells, but recently has been found to be expressed in some forms of cancers including colon and breast cancers, and melanoma, and human cancer cell lines. Overexpression of Del1 accelerates tumor growth by enhancing vascular formation, implying Del1 may be a potential target for anti-angiogenic cancer therapy. The study aims to investigate whether downregulation of Del1 could inhibit the growth of tumors established in nude Balb/c mice by subcutaneous implantation of human LS-174T colon cancer cells. The shRNA expression vectors targeting human Del1, and vascular endothelial growth factor (VEGF) were constructed. Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro. Gene transfection of VEGF-shRNA downregulated expression of both VEGF and Del1 in LS-174T cells in vivo and in vitro. Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation. Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.
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ABSTRACT: Integrins are a class of cell adhesion molecules that regulate interactions between cells and their extracellular matrix (ECM). Several specific integrin receptors have been identified in intervertebral discs, including the fibronectin-binding integrin receptors alpha(5) beta(1), alpha(v) beta(3) and the collagen-binding integrin receptors alpha(1) beta(1), alpha(2) beta(1), and, alpha(v) beta(1). But the integrins expressions in degenerated intervertebral discs are still unknown. In our study, the expressions of alpha(1), alpha(2), alpha(5), alpha(v), beta(1), beta(3) integrin subunits, collagens, and fibronectin in normal and herniated intervertebral discs of human were determined. Specimens of human lumbar intervertebral discs were divided into 3 groups: normal discs (n = 10), protrusion (n = 15), and extrusion (n = 15). Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunoprecipitation were used to evaluate the alpha(1), alpha(2), alpha(5),alpha(v), beta(1), and beta(3) integrin subunits messenger ribonucleic acid (mRNA) and protein expressions. RT-PCR was also performed to measure the mRNA level of collagen I, collagen II, and fibronectin. The expressions of alpha(5) and beta(1) subunits were increased in herniated discs, especially in the discs of extrusion. But as to alpha(1), alpha(2), alpha(v) and beta(3), their expressions had no difference among the discs. Fibronectin, whose binding integrin receptor was alpha(5) beta(1) was also increased. And in herniated discs, the collagen I was increased, but the collagen II was decreased. The expressions of some integrin subunits were increased in herniated discs. These results may be attributed to the interaction between cells and the ECM in the process of degeneration.
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