Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model.
Osteosarcoma (OS) is a primary malignant bone tumor with a high propensity for local recurrence and distant metastasis. We previously showed a secreted, dominant-negative LRP5 receptor (DNLRP5) suppressed in vitro migration and invasion of the OS cell line SaOS-2. Therefore, we hypothesized DNLRP5 also has in vivo antitumor activity against OS. We used the 143B cell line as a model to study the effect of DNLRP5 by stable transfection. Inhibition of Wnt signaling by DNLRP5 was verified by a reduction in TOPFLASH luciferase activity. In soft agar, DNLRP5-transfected 143B cells formed fewer and smaller colonies than control transfected cells. DNLRP5 transfection reduced in vivo tumor growth of 143B cells in nude mice. DNLRP5 also decreased in vitro cellular motility in a scratch wound assay. In a spontaneous pulmonary metastasis model, DNLRP5 reduced both the size and number of lung metastatic nodules. The reduction in cellular invasiveness by DNLRP5 was associated with decreased expression of matrix metalloproteinase-2, N-cadherin, and Snail. Our data suggest canonical Wnt/LRP5 signaling reflects an important underlying mechanism of OS progression. Therefore, strategies to suppress LRP5-mediated signaling in OS cells may lead to a reduction in local or systemic disease burden.
Department of Orthopaedic Surgery, Musculoskeletal Oncology Laboratory, 101 The City Drive South, Orange, CA 92868, USA.
Yi
Y
Guo
Elyssa M
EM
Rubin
Jun
J
Xie
Xiaolin
X
Zi
Bang H
BH
Hoang
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay
D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse