A YKL-40-Neutralizing Antibody Blocks Tumor Angiogenesis and Progression: A Potential Therapeutic Agent in Cancers

被引:151
作者
Faibish, Michael [2 ]
Francescone, Ralph [2 ]
Bentley, Brooke [1 ]
Yan, Wei [3 ]
Shao, Rong [1 ,2 ,3 ]
机构
[1] Pioneer Valley Life Sci Inst, Springfield, MA 01199 USA
[2] Univ Massachusetts, Mol & Cellular Biol Program, Morrill Sci Ctr, Amherst, MA 01003 USA
[3] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA
关键词
HUMAN CARTILAGE GLYCOPROTEIN-39; METASTATIC BREAST-CANCER; SERUM YKL-40; ENDOTHELIAL-CELLS; MATRIX PROTEIN; SHORT SURVIVAL; BEVACIZUMAB; EXPRESSION; CHITINASE; VEGF;
D O I
10.1158/1535-7163.MCT-10-0868
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti-YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti-YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40-induced activation of the membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (Erk) 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to gamma-irradiation through decreased expression of pAKT and AKT and accordingly, abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with gamma-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has shown the therapeutic use for the mAY in treatment of tumor angiogenesis and metastasis. Mol Cancer Ther; 10(5); 742-51. (C) 2011 AACR.
引用
收藏
页码:742 / 751
页数:10
相关论文
共 43 条
[1]   Tumorigenesis and the angiogenic switch [J].
Bergers, G ;
Benjamin, LE .
NATURE REVIEWS CANCER, 2003, 3 (06) :401-410
[2]   High serum concentration of YKL-40 is associated with short survival in patients with acute myeloid leukemia [J].
Bergmann, OJ ;
Johansen, JS ;
Klausen, TW ;
Mylin, AK ;
Kristensen, JS ;
Kjeldsen, E ;
Johnsen, HE .
CLINICAL CANCER RESEARCH, 2005, 11 (24) :8644-8652
[3]   Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane [J].
Burstein, Harold J. ;
Elias, Anthony D. ;
Rugo, Hope S. ;
Cobleigh, Melody A. ;
Wolff, Antonio C. ;
Eisenberg, Peter D. ;
Lehman, Mary ;
Adams, Bonne J. ;
Bello, Carlo L. ;
DePrimo, Samuel E. ;
Baum, Charles M. ;
Miller, Kathy D. .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (11) :1810-1816
[4]   Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors [J].
Casanovas, O ;
Hicklin, DJ ;
Bergers, G ;
Hanahan, D .
CANCER CELL, 2005, 8 (04) :299-309
[5]   Serum YKL-40 and colorectal cancer [J].
Cintin, C ;
Johansen, JS ;
Christensen, IJ ;
Price, PA ;
Sorensen, S ;
Nielsen, HJ .
BRITISH JOURNAL OF CANCER, 1999, 79 (9-10) :1494-1499
[6]   High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival [J].
Cintin, C ;
Johansen, JS ;
Christensen, IJ ;
Price, PA ;
Sorensen, S ;
Nielsen, HJ .
CANCER, 2002, 95 (02) :267-274
[7]   YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes [J].
De Ceuninck, F ;
Gaufillier, S ;
Bonnaud, A ;
Sabatini, M ;
Lesur, C ;
Pastoureau, P .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2001, 285 (04) :926-931
[8]   Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis [J].
Ebos, John M. L. ;
Lee, Christina R. ;
Cruz-Munoz, William ;
Bjarnason, Georg A. ;
Christensen, James G. ;
Kerbel, Robert S. .
CANCER CELL, 2009, 15 (03) :232-239
[9]   VEGF and the quest for tumour angiogenesis factors [J].
Ferrara, N .
NATURE REVIEWS CANCER, 2002, 2 (10) :795-803
[10]  
FRANCESCONE RA, 2011, J BIOL CHEM