Dynamic analysis of lung metastasis by mouse osteosarcoma LM8: VEGF is a candidate for anti-metastasis therapy
Open Access
- 18 October 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Clinical & Experimental Metastasis
- Vol. 30 (4), 369-379
- https://doi.org/10.1007/s10585-012-9543-8
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis depends on pulmonary metastases, which arise from multi-step progression of malignant tumors. We herein aimed to clarify the critical step of pulmonary metastasis using the syngeneic mouse spontaneous highly metastatic OS LM8 and parental Dunn cell lines, to identify new candidate molecules to suppress pulmonary metastasis. We first investigated the chronological detection of circulating tumor cells (CTCs) from mice with either cell line. LM8 CTCs appeared faster, at a higher rate and with a greater number compared to Dunn CTCs. Cultured cells from CTCs of LM8 showed higher proliferative ability than cells from the primary site in suspension culture, which mimicked the environment of the bloodstream for CTCs. The proliferative ability of LM8 cells was also higher than that of Dunn cells in 3D collagen culture with low stiffness (−150 Pa; close to conditions in the lung). We next focused on the extravasation step. LM8 showed higher migration ability compared to Dunn with transendothelial migration assay. We also found a disruption in endothelial barrier function throughout co-culture with LM8 using time-lapse imaging. In addition, LM8 secreted high levels of vascular endothelial growth factor (VEGF), while VEGF signal inhibition with a small molecule tyrosine kinase inhibitor (pazopanib) decreased disruption of the vascular barrier and transendothelial migration of LM8. Finally, daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo. Collectively, these results show anti-VEGF therapy as a candidate for pulmonary metastasis of OS.Keywords
This publication has 38 references indexed in Scilit:
- Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical propertiesPhysical Biology, 2011
- Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor AngiogenesisCancer Cell, 2009
- Molecular Basis of MetastasisNew England Journal of Medicine, 2008
- Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate CancerClinical Cancer Research, 2008
- Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal CancerJournal of Clinical Oncology, 2008
- Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activityMolecular Cancer Therapeutics, 2007
- Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasisThe Journal of cell biology, 2004
- Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal CancerNew England Journal of Medicine, 2004
- Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis.2000
- The pathogenesis of cancer metastasisNature, 1980