title: Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma.
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.
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Krzysztof M
authors.initials: KM
authors.lastname: Mrozik
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Chee Man
authors.initials: CM
authors.lastname: Cheong
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: Hewett
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Annie W S
authors.initials: AW
authors.lastname: Chow
authors.affiliation: Division of Urology, Department of Surgery, McGill University, Montreal, Canada.
authors.forename: Orest W
authors.initials: OW
authors.lastname: Blaschuk
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.|Centre for Cancer Biology and Hanson Institute, SA Pathology, Adelaide, Australia.|School of Medicine, University of Adelaide, Adelaide, Australia.|Centre for Stem Cell Research, Robinson Institute, University of Adelaide, Adelaide, Australia.|Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, Australia.|Centre for Cancer Biology and Hanson Institute, SA Pathology, Adelaide, Australia.|School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
mesh_terms: D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*
chemical_list: C518575:ADH-1 pepide; D015820:Cadherins; C489083:Cdh2 protein, mouse; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010456:Peptides, Cyclic
keywords: ADH-1; N-cadherin; adhesion; extravasation; multiple myeloma