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Lymphangiogenesis and lymphatic vessel remodelling in cancer

Key Points

  • The lymphatic vasculature is essential for immune function, tissue fluid homeostasis and the absorption of dietary fat.

  • The process of lymphangiogenesis involves the formation of new lymphatic vessels from pre-existing lymphatics; this occurs during embryonic development, wound healing and in various pathological contexts, including cancer.

  • Tumour cells and cells of the tumour microenvironment produce growth factors that promote lymphangiogenesis from initial lymphatics, as well as the enlargement of initial and collecting lymphatic vessels in and around solid tumours. The enlargement of collecting lymphatics can involve remodelling of these vessels by smooth muscle cells.

  • Lymphangiogenic factors (such as vascular endothelial growth factor C (VEGFC) and VEGFD) can induce the metastatic spread of tumours in mouse models of cancer.

  • Clinicopathological studies have shown that the production of lymphangiogenic factors, lymphangiogenesis and lymphatic remodelling can correlate with cancer progression.

  • Lymphatic vessels provide a therapeutic target for modulating the immune response to cancer and restricting metastasis; clinical trials of agents that target lymphangiogenic signalling pathways are underway.

  • Mouse models and genome-wide functional screening approaches might identify further important signalling pathways in tumour lymphangiogenesis that could be potential diagnostic and therapeutic targets.

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.

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Figure 1: Structure of the lymphatic vasculature and of lymphatic endothelial cells from initial lymphatics.
Figure 2: Remodelling of lymphatic vessels in cancer and its contribution to metastasis.
Figure 3: Mechanisms of tumour lymphangiogenesis and interactions between tumour cells and lymphatics.
Figure 4: Lymphangiogenesis and lymphatic remodelling in cancer — implications for diagnostics.

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Acknowledgements

S.A.S., T.K. and M.G.A. are supported by Project Grants, a Program Grant and Research Fellowships from the National Health and Medical Research Council (NHMRC) of Australia, and by funds from the Operational Infrastructure Support Program that is provided by the Victorian Government, Australia. R.S. has been supported by the Raelene Boyle Sporting Chance Cancer Foundation and the Royal Australasian College of Surgeons (RACS) Foundation Scholarship, as well as the RACS Surgeon Scientist Program. S.P.W. has been supported by an Australian National Breast Cancer Foundation Doctoral Research Fellowship. The authors thank M. Macheda for proofreading.

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Correspondence to Steven A. Stacker or Marc G. Achen.

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Competing interests

S.A.S. and M.G.A. have both been consultants for Vegenics Limited, South Yarra, Victoria, Australia, in the area of developing inhibitors of angiogenesis and lymphangiogenesis in human diseases, including cancer. This consultancy ended on 31 December 2012. S.A.S., R.S. and M.G.A. are shareholders in Circadian Technologies (owner of Vegenics), South Yarra, Victoria, Australia, which is a company that develops anticancer therapeutics, and in Ark Therapeutics Group Plc, London, UK, which has been developing therapeutic approaches based on the vascular endothelial growth factor family. S.A.S., S.B.F. and M.G.A. are holders of an Australian National Health and Medical Research Council (NHMRC) Program Grant. S.A.S. and M.G.A. are holders of NHMRC Senior Research Fellowships in this area. S.A.S., S.B.F., T.K. and M.G.A. are holders of NHMRC Project Grants in this area. S.A.S. and M.G.A. are holders of numerous patents in this area. S.P.W. declares no competing interests.

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Glossary

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatics.

Lymphatic enlargement

The enlargement of lymphatics, which can occur via proliferation of lymphatic endothelial cells (that is, hyperplasia) or other non-proliferative mechanisms.

Lymphatic hyperplasia

The enlargement of lymphatics by proliferation of lymphatic endothelial cells, which may or may not be accompanied by sprouting.

Initial lymphatics

Small blind-ended lymphatics in the tissue periphery that are adapted for the uptake of fluid and cells.

Collecting lymphatics

Large lymphatics that are characterized by a continuous smooth muscle cell coating and are adapted for the transport of lymph and associated cells.

Lymphatic remodelling in cancer

Alteration to the structure and morphology of lymphatic vessels that are associated with cancer, including lymphangiogenesis and lymphatic enlargement.

Lymphatic invasion

The entry of tumour cells into lymphatics, which is identified clinicopathologically by the detection of tumour cells or tumour cell emboli within lymphatics.

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Stacker, S., Williams, S., Karnezis, T. et al. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14, 159–172 (2014). https://doi.org/10.1038/nrc3677

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