Frzb, a secreted wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of met signalling

被引:66
作者
Guo, Yi [1 ,2 ]
Me, Jun [1 ,2 ]
Rubin, Elyssa [1 ,2 ]
Tang, Ya-Xiong [1 ,3 ]
Lin, Fritz [4 ]
Zi, Xiaolin [1 ,3 ]
Hoang, Bang H. [1 ,2 ]
机构
[1] Univ Calif Irvine, Chao Family Comprehens Ctr, Irvine, CA 92868 USA
[2] Univ Calif Irvine, Dept Orthoped Surg, Irvine, CA USA
[3] Univ Calif Irvine, Dept Urol, Irvine, CA USA
[4] Univ Calif Irvine, Dept Pathol, Irvine, CA USA
关键词
D O I
10.1158/0008-5472.CAN-07-3220
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 (fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control-transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth,. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS.
引用
收藏
页码:3350 / 3360
页数:11
相关论文
共 46 条
[1]   Met, metastasis, motility and more [J].
Birchmeier, C ;
Birchmeier, W ;
Gherardi, E ;
Vande Woude, GF .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (12) :915-925
[2]   Matrix metalloproteinases participate in osteosarcoma invasion [J].
Bjornland, K ;
Flatmark, K ;
Pettersen, S ;
Aaasen, AO ;
Fodstad, O ;
Maelandsmo, GM .
JOURNAL OF SURGICAL RESEARCH, 2005, 127 (02) :151-156
[3]   Activation of Wnt signaling in the intestinal mucosa of Apc+/min mice does not cause overexpression of the receptor tyrosine kinase Met [J].
Boon, Elles M. J. ;
Pouwels, Walter ;
Redeker, Sandra ;
Joosten, Sander P. J. ;
Hamann, Jorg ;
van der Neut, Ronald ;
Pals, Steven T. .
CANCER SCIENCE, 2006, 97 (08) :710-715
[4]   Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis [J].
Christiansen, Jason J. ;
Rajasekaran, Ayyappan K. .
CANCER RESEARCH, 2006, 66 (17) :8319-8326
[5]   Medical progress: Soft-tissue sarcomas in adults [J].
Clark, MA ;
Fisher, C ;
Judson, I ;
Thomas, JM .
NEW ENGLAND JOURNAL OF MEDICINE, 2005, 353 (07) :701-711
[6]   Cancer therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations [J].
Coussens, LM ;
Fingleton, B ;
Matrisian, LM .
SCIENCE, 2002, 295 (5564) :2387-2392
[7]   The soluble Wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo [J].
DeAlmeida, Venita I. ;
Miao, Li ;
Ernst, James A. ;
Koeppen, Hartmut ;
Polakis, Paul ;
Rubinfeld, Bonnee .
CANCER RESEARCH, 2007, 67 (11) :5371-5379
[8]   The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition [J].
Dissanayake, Samudra K. ;
Wade, Michael ;
Johnson, Carrie E. ;
O'Connell, Michael P. ;
Leotlela, Poloko D. ;
French, Amanda D. ;
Shah, Kavita V. ;
Hewitt, Kyle J. ;
Rosenthal, Devin T. ;
Indig, Fred E. ;
Jiang, Yuan ;
Nickoloff, Brian J. ;
Taub, Dennis D. ;
Trent, Jeffrey M. ;
Moon, Randall T. ;
Bittner, Michael ;
Weeraratna, Ashani T. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (23) :17259-17271
[9]   Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas [J].
Entz-Werlé, N ;
Stoetzel, C ;
Berard-Marec, P ;
Brugiere, L ;
Pacquement, H ;
Schmitt, C ;
Tabone, MD ;
Gentet, JC ;
Quillet, R ;
Oudet, P ;
Lutz, P ;
Babin-Boilletot, A ;
Gaub, MP ;
Perrin-Schmitt, F .
INTERNATIONAL JOURNAL OF CANCER, 2005, 117 (03) :349-355
[10]  
FERRACINI R, 1995, ONCOGENE, V10, P739