Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis.

Abstract

Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here, we report evidence of critical role for the angiopoietin-like protein 2 (ANGPTL2) in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In patients with lung cancer, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor cell-derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor cell-derived ANGPTL2 accelerated metastasis and shortened survival whereas attenuating ANGPTL2 expression in tumor cells-blunted metastasis and extended survival. Overall, our findings showed that tumor cell-derived ANGPTL2 drives metastasis and provided an initial proof of concept for blockade of its action as a strategy to antagonize the metastatic process.

• Authors: Motoyoshi Endo, Masahiro Nakano, Tsuyoshi Kadomatsu, Shigetomo Fukuhara, Hiroaki Kuroda, Shuji Mikami, Tai Hato, Jun Aoi, Haruki Horiguchi, Keishi Miyata, Haruki Odagiri, Tetsuro Masuda, Masahiko Harada, Hirotoshi Horio, Tsunekazu Hishima, Hiroaki Nomori, Takaaki Ito, Yutaka Yamamoto, Takashi Minami, Seiji Okada, Takashi Takahashi, Naoki Mochizuki, Hirotaka Iwase, Yuichi Oike
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 7 Pg. 1784-94 (Apr 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22345152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• ANGPTL2 protein, human
• ATF2 protein, human
• Activating Transcription Factor 2
• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angiopoietins
• Angptl2 protein, mouse
• NFATC Transcription Factors
• NFATC1 protein, human
• Proto-Oncogene Proteins c-jun
• Vascular Endothelial Growth Factor A

Topics

• Activating Transcription Factor 2 (physiology)
• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angiopoietins (analysis, physiology)
• Animals
• Cell Line, Tumor
• Cell Movement
• Disease-Free Survival
• Humans
• Lung Neoplasms (mortality, pathology, secondary)
• Mammary Neoplasms, Experimental (pathology)
• Mice
• NFATC Transcription Factors (physiology)
• Neoplasm Metastasis
• Proto-Oncogene Proteins c-jun (physiology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)