Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia.
Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a beta-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-l-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 antiapoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC(50) of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.
Johnson
Kim D
KD
Department of Veterinary Pathobiology, Hematology/Oncology Division, University of Missouri-Columbia, Columbia, MO 65211, USA.
Glinskii
Olga V
OV
Mossine
Valeri V
VV
Turk
James R
JR
Mawhinney
Thomas P
TP
Anthony
Douglas C
DC
Henry
Carolyn J
CJ
Huxley
Virginia H
VH
Glinsky
Gennadi V
GV
Pienta
Kenneth J
KJ
Raz
Avraham
A
Glinsky
Vladislav V
VV
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006394:Hemangiosarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured