B7h Triggering Inhibits adhesiveness and migration of human umbilical vein endothelial cells and tumor cell lines Elena Boggio, Chiara Dianzani, Rosalba Minelli, Annalisa Chiocchetti, Casimiro Luca Gigliotti and Umberto Dianzani Vascular endothelial cells (EC) are key players in metastatic dissemination of tumor cells. ECs express B7h, which is the ligand of the ICOS T cell costimulatory molecule, and is also expressed by many cancer cell lines. The aim of this work was to assess the effect of B7h triggering by a soluble form of ICOS (ICOS-Fc) on the adhesion of cancer cell lines to EC using human umbilical vein EC (HUVEC) and the HT29, HCT116, DLD1 and Caco-2 (colon carcinoma), RPMI7932, JR8, M14, PCF2 (melanoma), HMC-1 (mastocytoma), PC3 (prostate carcinoma), and Hep-G2 (liver carcinoma) cell lines. Results showed that ICOS-Fc inhibited adhesion at high levels (> 40%) in PC3, Hep-G2, and HMC-1; at intermediate levels (30-40%) in JR8 and RPMI7932; whereas the effect was not significant (<25%) in M14, CaCo-2, and PCF2. The effect was detectable as early as 30 min after treatment, was still present after 24 h, and was exerted on both HUVEC and the cancer cell lines expressing B7h. It was inhibited by soluble anti-ICOS reagents (mAb and B7h-Fc) and silencing of B7h on HUVECs, and it was not displayed by an F119S mutated form of ICOS-Fc that does not bind B7h. HUVEC treatment with ICOS-Fc did not modulate expression of adhesion molecules and cytokines, but it substantially downmodulated ERK phosphorylation induced by E-selectin triggering or osteopontin, which may influence HUVEC adhesiveness. Since cell migration uses adhesive mechanisms, we also assessed whether ICOS-Fc influences cell migration assessed in Boyden chamber assays using HUVEC and the cancer cell lines (HT29, HCT116, PC-3, RPMI7932, JR8, M14, PCF2 and LM). Results showed that ICOS-Fc substantially inhibited migration of both HUVECs and all the cancer cell lines except RPMI7932, PCF2 and LM. Therefore, the B7h–ICOS interaction may modulate spreading of cancer metastases, which opens a view on the use of ICOS-Fc as an immunomodulatory drug.
B7h triggering inhibits adhesiveness and migration of human umbilical vein endothelial cells and tumour cell lines
DIANZANI, Chiara;MINELLI, ROSALBA;
2011-01-01
Abstract
B7h Triggering Inhibits adhesiveness and migration of human umbilical vein endothelial cells and tumor cell lines Elena Boggio, Chiara Dianzani, Rosalba Minelli, Annalisa Chiocchetti, Casimiro Luca Gigliotti and Umberto Dianzani Vascular endothelial cells (EC) are key players in metastatic dissemination of tumor cells. ECs express B7h, which is the ligand of the ICOS T cell costimulatory molecule, and is also expressed by many cancer cell lines. The aim of this work was to assess the effect of B7h triggering by a soluble form of ICOS (ICOS-Fc) on the adhesion of cancer cell lines to EC using human umbilical vein EC (HUVEC) and the HT29, HCT116, DLD1 and Caco-2 (colon carcinoma), RPMI7932, JR8, M14, PCF2 (melanoma), HMC-1 (mastocytoma), PC3 (prostate carcinoma), and Hep-G2 (liver carcinoma) cell lines. Results showed that ICOS-Fc inhibited adhesion at high levels (> 40%) in PC3, Hep-G2, and HMC-1; at intermediate levels (30-40%) in JR8 and RPMI7932; whereas the effect was not significant (<25%) in M14, CaCo-2, and PCF2. The effect was detectable as early as 30 min after treatment, was still present after 24 h, and was exerted on both HUVEC and the cancer cell lines expressing B7h. It was inhibited by soluble anti-ICOS reagents (mAb and B7h-Fc) and silencing of B7h on HUVECs, and it was not displayed by an F119S mutated form of ICOS-Fc that does not bind B7h. HUVEC treatment with ICOS-Fc did not modulate expression of adhesion molecules and cytokines, but it substantially downmodulated ERK phosphorylation induced by E-selectin triggering or osteopontin, which may influence HUVEC adhesiveness. Since cell migration uses adhesive mechanisms, we also assessed whether ICOS-Fc influences cell migration assessed in Boyden chamber assays using HUVEC and the cancer cell lines (HT29, HCT116, PC-3, RPMI7932, JR8, M14, PCF2 and LM). Results showed that ICOS-Fc substantially inhibited migration of both HUVECs and all the cancer cell lines except RPMI7932, PCF2 and LM. Therefore, the B7h–ICOS interaction may modulate spreading of cancer metastases, which opens a view on the use of ICOS-Fc as an immunomodulatory drug.
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