The metastasis of tumour cells is a leading cause of mor- tality in cancer patients and occurs through lymphatic vessels and blood vessels. The presence of tumour cells in regional or sentinel lymph nodes (SLNs) is a key pre- dictor of poor outcome in human cancer 1 , which illus- trates the relevance of lymphatics to cancer biology. It was previously thought that the lymphatic vasculature had a passive role in cancer metastasis; however, experi- mental and clinicopathological studies indicate that lymphatic vessels undergo dynamic changes that facili- tate metastasis. These changes include lymphangiogenesis and lymphatic enlargement (which can occur through lymphatic hyperplasia), and they involve initial lymphatics around the primary tumour. These events are thought to favour entry of tumour cells into the lymphatic vascula- ture 2–5 . The enlargement of collecting lymphatics that are proximal or distal to SLNs, which is a process that can involve proliferation of lymphatic endothelial cells (LECs), other non-proliferative mechanisms and altera- tions to lymphatic-associated vascular smooth muscle cells (LVSMCs), has also been reported and is thought to facilitate the dissemination of tumour cells 6,7 . Moreover, lymphangiogenesis in tumour-draining lymph nodes might increase the spread of tumour cells to distant sites in the body 8 . The recognition that lymphangiogenesis and lymph- atic remodelling are functionally important in cancer has led to the idea that blocking them, by targeting lymphangiogenic signalling pathways, might be a use- ful therapeutic strategy to restrict metastatic spread 9 . Furthermore, the remodelling of tumour-associated lymphatics and of lymphatics in tumour-draining lymph nodes might provide prognostic opportuni- ties 10 . In this Review we discuss lymphangiogenesis and lymphatic remodelling in cancer, and we focus on recent progress in defining the molecular and cellular mecha- nisms that control these processes. The implications of these findings for the development of new diagnostics and therapeutics, and for future cancer research, are also discussed. Structure of the lymphatic system Although the structure and physiology of the lymphatic system have been studied since the Renaissance 11 , advances in identifying molecular markers of lymph- atics (BOX 1), which have predominantly occurred over the past 20 years, have focused on the unique cellular and functional features of this system and its role in pathology. The lymphatic vasculature is essential for immune function, tissue fluid homeostasis and for the absorption of dietary fat. Starting as small blind-ended vessels that absorb fluid and cells in tissues 12,13 , the ini- tial lymphatics are characterized by short anchoring filaments, which connect the abluminal membrane of LECs to the surrounding elastic fibres in the tissue 12 (FIG. 1). These lymphatics have an intermittent basement membrane and no pericytes or VSMCs. The tethering of LECs to elastic fibres, as well as unique discontinu- ous ‘button-like’ cell–cell junctions between LECs allow flaps of the vessel to open and fluid to enter but not to leave. The anchoring filaments are particularly impor- tant when the interstitial fluid pressure is increased 1 Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3010, Australia. 3 Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia. 4 Department of Surgery, St. Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia. 5 O’Brien Institute, Australian Catholic University, Fitzroy, Victoria 3065, Australia. 6 Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. Correspondence to S.A.S. and M.G.A.  e‑mails: Steven.stacker@ petermac.org; Marc.achen@petermac.org doi:10.1038/nrc3677 Published online 13 February 2014 Lymphangiogenesis and lymphatic vessel remodelling in cancer Steven A. Stacker 1–3 , Steven P. Williams 1 , Tara Karnezis 1,2 , Ramin Shayan 1,3–5 , Stephen B. Fox 2,6 and Marc G. Achen 1–3 Abstract | The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer. REVIEWS NATURE REVIEWS | CANCER VOLUME 14 | MARCH 2014 | 159 © 2014 Macmillan Publishers Limited. All rights reserved