Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma

Krzysztof M. Mrozik, Chee Man Cheong, Duncan Hewett, Annie W S Chow, Orest W. Blaschuk, Andrew C W Zannettino, Kate Vandyke

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 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.

LanguageEnglish
Pages387-399
Number of pages13
JournalBritish Journal of Haematology
Volume171
Issue number3
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

  • ADH-1
  • Adhesion
  • Extravasation
  • Multiple myeloma
  • N-cadherin

ASJC Scopus subject areas

  • Hematology

Cite this

Mrozik, Krzysztof M. ; Cheong, Chee Man ; Hewett, Duncan ; Chow, Annie W S ; Blaschuk, Orest W. ; Zannettino, Andrew C W ; Vandyke, Kate. / Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma. In: British Journal of Haematology. 2015 ; Vol. 171, No. 3. pp. 387-399.
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Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma. / Mrozik, Krzysztof M.; Cheong, Chee Man; Hewett, Duncan; Chow, Annie W S; Blaschuk, Orest W.; Zannettino, Andrew C W; Vandyke, Kate.

In: British Journal of Haematology, Vol. 171, No. 3, 01.11.2015, p. 387-399.

Research output: Contribution to journalArticle

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