The involvement of stromal derived factor 1alpha in homing and progression of multiple myeloma in the 5TMM model.
OBJECTIVE
Multiple myeloma (MM) is a lethal plasma cell cancer characterized by the monoclonal growth of cells in the bone marrow. To reach the bone marrow, MM cells need to be attracted by chemokines. Recently, it has been shown that chemokines can also be involved in the growth of several cancer types. Stromal cell derived factor 1a (SDF1alpha) or CXCL12 is known to play an important role as a chemokine for hematopoietic progenitor cells and human MM cells. We studied the effects of SDF1a in the 5TMM murine model.


METHODS
The in vitro effects of SDF1alpha were analyzed by gelatin zymography, adhesion, migration, proliferation, and chemoinvasion assays and by blockade with the CXCR4 inhibitor, 4F-benzoyl-TN14003. In vivo, diseased mice were treated with either vehicle or 4F-benzoyl-TN14003.


RESULTS
In vitro SDF1alpha was capable of attracting both 5T2MM and 5T33MM cells and inducing a 1.6-fold increase in MMP9 production by the 5TMM cells, which was correlated with an increased invasive capacity. In addition, SDF1alpha induced a 20% increase in DNA synthesis in the 5TMM cells. All these effects could be blocked by the CXCR4 inhibitor, 4Fbenzoyl- TN14003. An in vivo study in the 5T33MM model showed that blocking CXCR4 led to a 20% reduction in bone marrow tumor load.


CONCLUSIONS
These data demonstrate that SDF1alpha/CXCR4 is involved in the homing and the expansion of MM cells. Blocking CXCR4 could be useful in synergy with other anti-neoplastic treatments targeting the bone marrow microenvironment.
Menu
Eline
E
Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Asosingh
Kewal
K
Indraccolo
Stefano
S
De Raeve
Hendrik
H
Van Riet
Ivan
I
Van Valckenborgh
Els
E
Vande Broek
Isabelle
I
Van de Broek
Isabelle
I
Fujii
Nobutaka
N
Tamamura
Hirokazu
H
Van Camp
Ben
B
Vanderkerken
Karin
K
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
C477728:4-fluorobenzoyl-TN-14003; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D009363:Neoplasm Proteins; D010455:Peptides; D019718:Receptors, CXCR4; D020780:Matrix Metalloproteinase 9