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|Title:||Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma|
|Citation:||British Journal of Haematology, 2015; 171(3):387-399|
|Krzysztof M. Mrozik, Chee Man Cheong, Duncan Hewett, Annie W.S. Chow, Orest W. Blaschuk, Andrew C.W. Zannettino and Kate Vandyke|
|Abstract:||Elevated expression of the cell adhesion molecule N-cadherin (cadherin 2, type 1, N-cadherin (neuronal); CDH2) is associated with poor prognosis in newly-diagnosed multiple myeloma (MM) patients. In this study, we investigated whether targeting of N-cadherin represents a potential treatment for the ~50% of MM patients with elevated N-cadherin. Initially, we stably knocked-down N-cadherin in the mouse MM plasma cell (PC) line 5TGM1 to assess the functional role of N-cadherin in MM pathogenesis. When compared with 5TGM1-scramble-shRNA cells, 5TGM1-Cdh2-shRNA cells had significantly reduced adhesion to bone marrow endothelial cells. However, N-cadherin knock-down did not affect 5TGM1 cell proliferation or adhesion to bone marrow stromal cells. In the C57BL/KaLwRij murine MM model, mice intravenously inoculated with 5TGM1-Cdh2-shRNA cells showed significantly decreased tumour burden after 4 weeks, compared with animals bearing 5TGM1-scramble-shRNA cells. Finally, the N-cadherin antagonist ADH-1 had no effect on tumour burden in the established disease setting, whereas up-front ADH-1 treatment resulted in significantly reduced tumour burden after 4 weeks. Our findings demonstrate that Ncadherin may play a key role in the extravasation of circulating MM PCs promoting bone marrow homing. Moreover, these studies suggest that Ncadherin may represent a viable therapeutic target to prevent the dissemination of MM PCs and delay MM disease progression.|
|Keywords:||multiple myeloma; N-cadherin; adhesion; extravasation; ADH-1|
|Rights:||© 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 387–399|
|Appears in Collections:||Medicine publications|
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