Frzb, a secreted Wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of Met signaling.
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.
Guo
Yi
Y
Department of Orthopedic Surgery, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92868, USA.
Xie
Jun
J
Rubin
Elyssa
E
Tang
Ya-Xiong
YX
Lin
Fritz
F
Zi
Xiaolin
X
Hoang
Bang H
BH
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000099274:Frizzled-Related Proteins
D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins; C491743:MET protein, human