Paul V Senior1, Benny X Zhang, Steven T F Chan. 1. Department of Surgery, University of Melbourne, Western Hospital, Gordon Street, Footscray, Victoria 3011, Australia. psenior@unimelb.edu.au
Abstract
PURPOSE: In normal colonic epithelium, the receptor tyrosine kinase, EphB2 interacts with ephrinB1 ligand to maintain the integrity and architecture of the colonic crypt. Loss of EphB2 is seen in most colorectal cancers and correlates with poor prognosis. In this study, we investigated the effects of two levels of EphB2 expression on cell migration and invasion in a colon cancer cell line and on the growth of tumour xenografts. METHODS: An EphB2-negative colon cancer cell line (LIM2405) was transfected with a full-length EphB2 cDNA in a vector designed to respond to the drug tetracycline. The effect of two levels of EphB2 expression on the ability of cells to migrate through a porous barrier in response to a chemo-attractant and to invade through artificial basement membranes was tested in vitro. Finally, the effects of two expression levels of EphB2 on tumour growth using an in vivo model of colonic tumour xenograft in a mouse model were assessed. RESULTS: Expression of moderate levels of EphB2 significantly reduced the migration of tumour cells compared to control (p < 0.05, Kruskal-Wallis test). Expression of high levels of EphB2 further reduced migration of tumour cells (p < 0.05, Kruskal-Wallis test). Similarly, expression of EphB2 markedly reduces the invasive ability of tumour cells. The in vivo model of tumour growth showed that tumours with the highest level of EphB2 expression had a reduced risk of reaching a 10-mm size (defined event) compared with the control group (Cox regression, hazard ratio (HR) = 0.052, 95% CI 0.005-0.550; p = 0.014). Tumours derived from EphB2 expressing cells had a significantly reduced number of mitotic figures (p < 0.05) and an increased number of apoptotic cells (p < 0.05) compared to tumours from control cells. CONCLUSION: Even a moderate level of EphB2 expression has effects on tumour cells which results in reduced migration and invasiveness and slows the growth of colonic tumour implants in an in vivo model.
PURPOSE: In normal colonic epithelium, the receptor tyrosine kinase, EphB2 interacts with ephrinB1 ligand to maintain the integrity and architecture of the colonic crypt. Loss of EphB2 is seen in most colorectal cancers and correlates with poor prognosis. In this study, we investigated the effects of two levels of EphB2 expression on cell migration and invasion in a colon cancer cell line and on the growth of tumour xenografts. METHODS: An EphB2-negative colon cancer cell line (LIM2405) was transfected with a full-length EphB2 cDNA in a vector designed to respond to the drug tetracycline. The effect of two levels of EphB2 expression on the ability of cells to migrate through a porous barrier in response to a chemo-attractant and to invade through artificial basement membranes was tested in vitro. Finally, the effects of two expression levels of EphB2 on tumour growth using an in vivo model of colonic tumour xenograft in a mouse model were assessed. RESULTS: Expression of moderate levels of EphB2 significantly reduced the migration of tumour cells compared to control (p < 0.05, Kruskal-Wallis test). Expression of high levels of EphB2 further reduced migration of tumour cells (p < 0.05, Kruskal-Wallis test). Similarly, expression of EphB2 markedly reduces the invasive ability of tumour cells. The in vivo model of tumour growth showed that tumours with the highest level of EphB2 expression had a reduced risk of reaching a 10-mm size (defined event) compared with the control group (Cox regression, hazard ratio (HR) = 0.052, 95% CI 0.005-0.550; p = 0.014). Tumours derived from EphB2 expressing cells had a significantly reduced number of mitotic figures (p < 0.05) and an increased number of apoptotic cells (p < 0.05) compared to tumours from control cells. CONCLUSION: Even a moderate level of EphB2 expression has effects on tumour cells which results in reduced migration and invasiveness and slows the growth of colonic tumour implants in an in vivo model.
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