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Therapeutic targeting of N‐cadherin is an effective treatment for multiple myeloma
Author(s) -
Mrozik Krzysztof M.,
Cheong Chee Man,
Hewett Duncan,
Chow Annie W.S.,
Blaschuk Orest W.,
Zannettino Andrew C.W.,
Vandyke Kate
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13596
Subject(s) - cadherin , stromal cell , bone marrow , medicine , multiple myeloma , extravasation , small hairpin rna , homing (biology) , cancer research , pathogenesis , pathology , cell culture , cell , chemistry , biology , gene knockdown , ecology , biochemistry , genetics
Summary Elevated expression of the cell adhesion molecule N‐cadherin (cadherin 2, type 1, N‐cadherin (neuronal); CDH 2) 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 5 TGM 1 to assess the functional role of N‐cadherin in MM pathogenesis. When compared with 5 TGM 1‐scramble‐sh RNA cells, 5 TGM 1‐ Cdh2 ‐sh RNA cells had significantly reduced adhesion to bone marrow endothelial cells. However, N‐cadherin knock‐down did not affect 5 TGM 1 cell proliferation or adhesion to bone marrow stromal cells. In the C57 BL /KaLwRij murine MM model, mice intravenously inoculated with 5 TGM 1‐ Cdh2 ‐sh RNA cells showed significantly decreased tumour burden after 4 weeks, compared with animals bearing 5 TGM 1‐scramble‐sh RNA 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 PC s promoting bone marrow homing. Moreover, these studies suggest that N‐cadherin may represent a viable therapeutic target to prevent the dissemination of MM PC s and delay MM disease progression.