Notch signaling drives multiple myeloma induced osteoclastogenesis

Colombo, M. et al. (2014) Notch signaling drives multiple myeloma induced osteoclastogenesis. Oncotarget, 5(21), pp. 10393-10406. (doi: 10.18632/oncotarget.2084) (PMID:25257302) (PMCID:PMC4279381)

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Abstract

Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Muecklisch, Dr Katja and Akbar, Mr Moeed and Soutar, Dr Richard and Goodyear, Professor Carl
Authors: Colombo, M., Thümmler, K., Mirandola, L., Garavelli, S., Todoerti, K., Apicella, L., Lazzari, E., Lancellotti, M., Platonova, N., Akbar, M., Chiriva-Internati, M., Soutar, R., Neri, A., Goodyear, C. S., and Chiaramonte, R.
Subjects:Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Research Group:Goodyear
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Oncotarget 5(21): 10393-10406
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
559981The simultaneous targeting of inflammatory and osteoglastogenic mechanisms in rheumatoid arthritisCarl GoodyearArthritis Research UK (ARUK)MP/19701III -IMMUNOLOGY
603941Targeting bone disease in myelomaCarl GoodyearAssociation for International Cancer Research (AICR)13-1215III -IMMUNOLOGY
522271Inhibition of osteoclastogenesis by immunomodulatory complexesCarl GoodyearMedical Research Scotland (MED-SCOT)349 FRGIII -IMMUNOLOGY