Tumor metastasis represents a major cause of cancer mortality. Despite intense effort, strategies designed to inhibit metastasis have been unsuccessful, in part due to lack of understanding of mechanisms underlying the process. In this study, a shortened period of disease-free survival was observed after surgery in lung cancer patients showing high angiopoietin-like protein 2 (ANGPTL2) expression in tumor cells within primary tumor sites. Furthermore, tumor cell–derived ANGPTL2 increased tumor cell motility and invasive capacity in an autocrine/paracrine manner, resulting in acquisition of metastatic tumor phenotypes. In tumor cell–implanted mouse models, tumor cell–derived ANGPTL2 accelerated metastasis and shortened survival periods; conversely, decreasing ANGPTL2 expression in tumor cells significantly attenuated metastasis and extended survival periods. This image represents CD44-stained human breast tumor cells expressing ANGPTL2 in lung metastasis in mice. For details, see the article by Endo and colleagues on page 1784 of this issue.