The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases

Haruki Odagiri, Tsuyoshi Kadomatsu, Motoyoshi Endo, Tetsuro Motoyoshi, Masaki Suimye Morioka, Shigetomo Fukuhara, Takeshi Miyamoto, Eisuke Kobayashi, Keishi Miyata, Jun Aoi, Haruki Horiguchi, Naotaka Nishimura, Kazutoyo Terada, Toshitake Yakushiji, Ichiro Manabe, Naoki Mochizuki, Hiroshi Mizuta, Yuichi Oike

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Abstract

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.

Original languageEnglish
Pages (from-to)ra7
JournalScience Signaling
Volume7
Issue number309
DOIs
Publication statusPublished - 2014 Jan 21

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Odagiri, H., Kadomatsu, T., Endo, M., Motoyoshi, T., Morioka, M. S., Fukuhara, S., Miyamoto, T., Kobayashi, E., Miyata, K., Aoi, J., Horiguchi, H., Nishimura, N., Terada, K., Yakushiji, T., Manabe, I., Mochizuki, N., Mizuta, H., & Oike, Y. (2014). The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases. Science Signaling, 7(309), ra7. https://doi.org/10.1126/scisignal.2004612