TY - JOUR
T1 - The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases
AU - Odagiri, Haruki
AU - Kadomatsu, Tsuyoshi
AU - Endo, Motoyoshi
AU - Motoyoshi, Tetsuro
AU - Morioka, Masaki Suimye
AU - Fukuhara, Shigetomo
AU - Miyamoto, Takeshi
AU - Kobayashi, Eisuke
AU - Miyata, Keishi
AU - Aoi, Jun
AU - Horiguchi, Haruki
AU - Nishimura, Naotaka
AU - Terada, Kazutoyo
AU - Yakushiji, Toshitake
AU - Manabe, Ichiro
AU - Mochizuki, Naoki
AU - Mizuta, Hiroshi
AU - Oike, Yuichi
PY - 2014/1/21
Y1 - 2014/1/21
N2 - The tumor microenvironment can enhance the invasive capacity of tumor cells. We showed that expression of angiopoietin-like protein 2 (ANGPTL2) in osteosarcoma (OS) cell lines increased and the methylation of its promoter decreased with time when grown as xenografts in mice compared with culture. Compared with cells grown in normal culture conditions, the expression of genes encoding DNA demethylation-related enzymes increased in tumor cells implanted into mice or grown in hypoxic,serum-starved culture conditions. ANGPTL2 expression in OS cell lines correlated with increased tumor metastasis and decreased animal survival by promoting tumor cell intravasation mediated by the integrin α5β1, p38 mitogen-activated protein kinase, and matrix metalloproteinases. The tolloid-like 1 (TLL1)protease cleaved ANGPTL2 into fragments in vitro that did not enhance tumor progression when overexpressed in xenografts. Expression of TLL1 was weak in OS patient tumors, suggesting that ANGPTL2 may not be efficiently cleaved upon secretion from OS cells. These findings demonstrate that preventing ANGPTL2 signaling stimulated by the tumor microenvironment could inhibit tumor cell migration and metastasis.
AB - The tumor microenvironment can enhance the invasive capacity of tumor cells. We showed that expression of angiopoietin-like protein 2 (ANGPTL2) in osteosarcoma (OS) cell lines increased and the methylation of its promoter decreased with time when grown as xenografts in mice compared with culture. Compared with cells grown in normal culture conditions, the expression of genes encoding DNA demethylation-related enzymes increased in tumor cells implanted into mice or grown in hypoxic,serum-starved culture conditions. ANGPTL2 expression in OS cell lines correlated with increased tumor metastasis and decreased animal survival by promoting tumor cell intravasation mediated by the integrin α5β1, p38 mitogen-activated protein kinase, and matrix metalloproteinases. The tolloid-like 1 (TLL1)protease cleaved ANGPTL2 into fragments in vitro that did not enhance tumor progression when overexpressed in xenografts. Expression of TLL1 was weak in OS patient tumors, suggesting that ANGPTL2 may not be efficiently cleaved upon secretion from OS cells. These findings demonstrate that preventing ANGPTL2 signaling stimulated by the tumor microenvironment could inhibit tumor cell migration and metastasis.
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U2 - 10.1126/scisignal.2004612
DO - 10.1126/scisignal.2004612
M3 - Article
C2 - 24448647
AN - SCOPUS:84893040697
VL - 7
SP - ra7
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 309
ER -