Abstract
Whereas the role of the G-protein-coupled APJ receptor and its ligand, apelin, in angiogenesis has been well documented, the ability of the apelin/APJ system to induce lymphangiogenesis and lymphatic metastasis has been largely unexplored. To this end, we first show that APJ is expressed in lymphatic endothelial cells (LECs) and, moreover, that it responds to apelin by activating the apelinergic signaling cascade. We find that although apelin treatment does not influence the proliferation of LECs in vitro, it enhances their migration, protects them against UV irradiation-induced apoptosis, increases their spheroid numbers in 3D culture, stimulates their in vitro capillary-like tube formation and, furthermore, promotes the invasive growth of lymphatic microvessels in vivo in the matrigel plug assay. We also demonstrate that apelin overexpression in malignant cells is associated with accelerated in vivo tumor growth and with increased intratumoral lymphangiogenesis and lymph node metastasis. These results indicate that apelin induces lymphangiogenesis and, accordingly, plays an important role in lymphatic tumor progression. Our study does not only reveal apelin as a novel lymphangiogenic factor but might also open the door for the development of novel anticancer therapies targeting lymphangiogenesis.
Highlights
The lymphatic system is essential for maintaining interstitial fluid homeostasis, immune cell trafficking and lipid transport
Recent studies on lymphangiogenesis have been focused on two molecules of the VEGF family, VEGF-C and -D, which are the ligands for VEGFR-3 (VEGF receptor-3) [1, 3]
We provide evidence that apelin acts both in vitro and in vivo as a lymphangiogenic factor and, that it has an important role in lymph node (LN) metastasis
Summary
The lymphatic system is essential for maintaining interstitial fluid homeostasis, immune cell trafficking and lipid transport. The lymphatic network has an active role in different pathological conditions including tissue www.impactjournals.com/oncotarget inflammation, wound healing, renal and corneal graft rejection [1] but lymphatics are insufficient in patients with primary or secondary lymphoedema [2]. Lymphatic spread frequently occurs in solid malignancies and is considered an indicator of local dissemination and poor prognosis, a long-established concept has assigned a passive role to lymphatics in tumor progression. Recent animal studies using lymphangiogenic molecules have indicated that lymphatic vessels interact extensively with malignant cells and, that lymphangiogenesis is associated with, and can enhance, lymph node (LN) metastasis. The most widely studied molecular system that facilitates the expansion of the lymphatic network both under physiological and pathological conditions is the VEGF-C/ -D / VEGFR-3 signaling pathway. Our knowledge of the molecular mechanisms that underlie lymphangiogenesis still lags far behind that of the vascular system [3]
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