Constitutive expression of IL-12R beta 2 on human multiple myeloma cells delineates a novel therapeutic target.
The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12R beta 2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12R beta 2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12R beta 2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCI-H929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-gamma, IFN-alpha, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-gamma-related antiangiogenic pathway. Thus, IL-12R beta 2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.
Airoldi
Irma
I
Department of Experimental and Laboratory Medicine, G. Gaslini Institute, Genova, Italy. irmaairoldi@ospedale-gaslini.ge.it
Cocco
Claudia
C
Giuliani
Nicola
N
Ferrarini
Marina
M
Colla
Simona
S
Ognio
Emanuela
E
Taverniti
Giuseppe
G
Di Carlo
Emma
E
Cutrona
Giovanna
G
Perfetti
Vittorio
V
Rizzoli
Vittorio
V
Ribatti
Domenico
D
Pistoia
Vito
V
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009101:Multiple Myeloma / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000032:analysis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C508439:IL12RB2 protein, human; D053707:Receptors, Interleukin-12; D018664:Interleukin-12