Therapeutic targeting of N‐cadherin is an effective treatment for multiple myeloma. (20th July 2015)

• Record Type: Journal Article
• Authors: Mrozik, Krzysztof M.; Cheong, Chee Man; Hewett, Duncan; Chow, Annie W.S.; Blaschuk, Orest W.; Zannettino, Andrew C.W.; Vandyke, Kate
• Is Part Of: British journal of haematology. Volume 171:Number 3(2015:Nov.)
• Page Start: 387
• Page End: 399
• Publication Date: 2015-07-20
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13596
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh13596-abs-0001"> <title>Summary</title> <p>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‐<italic>Cdh2</italic>‐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‐<italic>Cdh2</italic>‐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 N‐cadherin may play a key role in the extravasation of circulating MM PCs promoting bone marrow homing. Moreover, these studies suggest that N‐cadherin may represent a viable therapeutic target to prevent the dissemination of MM PCs and delay MM disease progression.</p> </abstract>