Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.
Galectin-1 (Gal-1) is involved in tumoral angiogenesis, hypoxia and metastases. Actually the Gal-1 expression profile in multiple myeloma (MM) patients and its pathophysiological role in MM-induced angiogenesis and tumoral growth are unknown. In this study, we found that Gal-1 expression by MM cells was upregulated in hypoxic conditions and that stable knockdown of hypoxia inducible factor-1α significantly downregulated its expression. Therefore, we performed Gal-1 inhibition using lentivirus transfection of shRNA anti-Gal-1 in human myeloma cell lines (HMCLs), and showed that its suppression modified transcriptional profiles in both hypoxic and normoxic conditions. Interestingly, Gal-1 inhibition in MM cells downregulated proangiogenic genes, including MMP9 and CCL2, and upregulated the antiangiogenic ones SEMA3A and CXCL10. Consistently, Gal-1 suppression in MM cells significantly decreased their proangiogenic properties in vitro. This was confirmed in vivo, in two different mouse models injected with HMCLs transfected with anti-Gal-1 shRNA or the control vector. Gal-1 suppression in both models significantly reduced tumor burden and microvascular density as compared with the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on X-ray in the intratibial model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM blocking angiogenesis.
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
P
P
Storti
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
V
V
Marchica
'Laboratorio di Oncologia', Istituto Giannina Gaslini, Genova, Italy.
I
I
Airoldi
Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
G
G
Donofrio
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
E
E
Fiorini
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
V
V
Ferri
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
D
D
Guasco
Laboratory of Pre-clinical and Translational Research, IRCCS, Rionero in Vulture, Italy.
K
K
Todoerti
Hematology, Indiana University, Indianapolis, IN, USA.
R
R
Silbermann
Hematology, Indiana University, Indianapolis, IN, USA.
J L
JL
Anderson
Hematology, Indiana University, Indianapolis, IN, USA.
W
W
Zhao
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
L
L
Agnelli
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
M
M
Bolzoni
Pathology, 'Azienda Ospedaliero-Universitaria', Parma, Italy.
E
E
Martella
Pathology, 'Azienda Ospedaliero-Universitaria', Parma, Italy.
C
C
Mancini
Pathology, 'Azienda Ospedaliero-Universitaria', Parma, Italy.
N
N
Campanini
Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
D M
DM
Noonan
Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
P G
PG
Petronini
Pathology, 'Azienda Ospedaliero-Universitaria', Parma, Italy.|Hematology Unit, 'Fondazione IRCCS Ca' Granda', 'Ospedale Maggiore Policlinico', Milan, Italy.
A
A
Neri
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology and BMT Center, CoreLab, 'Azienda Ospedaliero-Universitaria', Parma, Italy.
F
F
Aversa
Hematology, Indiana University, Indianapolis, IN, USA.|Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
G D
GD
Roodman
Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Hematology and BMT Center, CoreLab, 'Azienda Ospedaliero-Universitaria', Parma, Italy.
N
N
Giuliani
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D037483:Galectin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
D037483:Galectin 1; D034741:RNA, Small Interfering