Identification of molecular mechanisms underlying lymphangiogenesis and angiogenesis in tumor progression and metastasis

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Despite intense effort, strategies designed to inhibit tumor cell metastasis have been unsuccessful because of lack of understanding of mechanisms underlying the process. Here we report that increases in expression and secretion of angiopoietin-like protein 2 (Angptl2) by primary tumors are highly correlated with the frequency of tumor metastasis both in patients and in tumor cell-implanted mouse models. Tumor cell-derived Angptl2 accelerates metastasis by activating tumor angiogenesis and lymphangiogenesis. Angptl2 expressed in tumor cells was induced by hypoxia and undernutrition, suggesting that the tumor microenvironment induces a tumor cell-derived Angptl2 signal that promotes metastasis. Conversely, targeted deletion of Angptl2 in tumor cells significantly decreased metastasis in tumor cell-implanted mouse models. Based on the present findings we propose that Angptl2 functions as a key regulator of tumor metastasis. These studies could form the basis of new treatment strategies to antagonize tumor metastasis.