The secreted protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin α5β1, p38 MAPK, and matrix metalloproteinases.
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.
1Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Haruki
H
Odagiri
Tsuyoshi
T
Kadomatsu
Motoyoshi
M
Endo
Tetsuro
T
Masuda
Masaki Suimye
MS
Morioka
Shigetomo
S
Fukuhara
Takeshi
T
Miyamoto
Eisuke
E
Kobayashi
Keishi
K
Miyata
Jun
J
Aoi
Haruki
H
Horiguchi
Naotaka
N
Nishimura
Kazutoyo
K
Terada
Toshitake
T
Yakushiji
Ichiro
I
Manabe
Naoki
N
Mochizuki
Hiroshi
H
Mizuta
Yuichi
Y
Oike
D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D064593:Heterografts; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D012516:Osteosarcoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D059016:Tumor Microenvironment; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D039081:Integrin alpha5beta1; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases