title: 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.affiliation: Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kuroda
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Tai
authors.initials: T
authors.lastname: Hato
authors.forename: Jun
authors.initials: J
authors.lastname: Aoi
authors.forename: Haruki
authors.initials: H
authors.lastname: Horiguchi
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Haruki
authors.initials: H
authors.lastname: Odagiri
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Masuda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Harada
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Horio
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Hishima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomori
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D051698:Activating Transcription Factor 2 / Q000502:physiology; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000032:analysis / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D050778:NFATC Transcription Factors / Q000502:physiology; D009362:Neoplasm Metastasis; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: C485792:ANGPTL2 protein, human; C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D042461:Vascular Endothelial Growth Factor A