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Metastasis

Lymphangiogenesis and cancer metastasis

Key Points

  • Tumour metastasis to regional lymph nodes is a crucial step in the progression of cancer. Detection of tumour cells in the lymph nodes is an indication of the spread of the tumour, and is used clinically as a prognostic tool and a guide to therapy. However, the molecular mechanisms that control the spread of cancer to the lymph nodes were unknown until recently.

  • The proliferation of new lymphatic vessels (lymphangiogenesis) is controlled, in part, by members of the vascular endothelial growth factor (VEGF) family — namely, VEGFC and VEGFD — and their cognate receptor on lymphatic endothelium, VEGFR3. These secreted growth factors are synthesized as propeptides that are activated by proteolysis to form high-affinity ligands that activate VEGFR3 and stimulate lymphangiogenesis.

  • The recent identification of molecular markers to discriminate between lymphatic endothelium and blood-vessel endothelium has enabled the study of lymphatic vessel formation in experimental models and in human tumours.

  • Experimental studies with VEGFC and VEGFD have shown that they can induce tumour lymphangiogenesis and direct metastasis to the lymphatic vessels and lymph nodes. By contrast, angiogenic factors such as VEGF act to enhance the growth of tumours by promoting a more extensive blood-vessel supply.

  • The published patterns of expression of lymphangiogenic factors in human tumours, in general, support the hypothesis that these factors promote the lymphatic spread of human tumours.

  • The inhibition of tumour lymphangiogenesis, using inhibitory agents that are directed to VEGFC, VEGFD or its receptor VEGFR3 (for example, monoclonal antibodies, receptor bodies or tyrosine kinase inhibitors), could be useful for anti-metastatic approaches to the treatment of human cancer.

Abstract

Lymphatic vessels are important for the spread of solid tumours, but the mechanisms that underlie lymphatic spread and the role of lymphangiogenesis (the growth of lymphatics) in tumour metastasis has been less clear. This article reviews recent experimental and clinico-pathological data indicating that growth factors that stimulate lymphangiogenesis in tumours are associated with an enhanced metastatic process.

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Figure 1: The protein structure of growth factors and receptors associated with lymphangiogenesis.
Figure 2: Mode of action of lymphangiogenic growth factors.
Figure 3: Function of lymphangiogenic factors in tumour biology.

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Acknowledgements

M.G.A. and S.A.S. are supported by the National Health and Medical Research Council of Australia and the Anti-Cancer Council of Victoria (ACCV). M.E.B. is supported by an ACCV postdoctoral fellowship. We thank J. Stickland for assistance with production of the figures.

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Correspondence to Kari Alitalo.

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DATABASES

Cancer.gov

breast cancer

colorectal cancer

gastric cancer

head and neck squamous-cell carcinoma

lung cancer

melanoma

non-small-cell lung cancer

oesophageal carcinoma

oropharyngeal carcinoma

prostate cancer

thyroid cancer

GenBank

SV40 T antigen

LocusLink

AKT

Ang2

CCL21

CD44

β-chemokine receptor D6

type IV collagen

desmoplakin

FOS

keratin 14

laminin

LYVE1

MAPK

neuropilin-2

placenta growth factor

Prox1

PROX1

TIE1

TIE2

VEGF

VEGFB

Vegfc

VEGFC

Vegfd

VEGFD

Vegfr2

VEGFR2

Vegfr3

VEGFR3

Glossary

LYMPHATIC VESSELS

The system of thin-walled, low-pressure vessels that collects fluid, proteins and cells that are released by the blood vessels into the interstitial spaces of tissues.

METASTASIS

The spread of malignant cells from the original site of the tumour. Spread occurs to such sites as the draining lymph nodes or to distant sites — typically the lung, liver or bone marrow in the case of solid tumours (for example, carcinomas — tumours of epithelial origin).

LYMPH NODE

A collection of lymphoid cells which occurs along the course of the lymphatics and serves to filter lymph (the fluid of the lymphatics) for antigen presentation and immune-cell proliferation. The lymph node is frequently the initial site to which tumours spread and is therefore an important diagnostic indicator.

ANGIOGENESIS

The proliferation of new blood vessels from pre-existing ones.

ENDOTHELIUM

The group of cells that line the inner surface of both the blood and lymphatic vessels. Endothelial cells can express specialized receptors that allow interaction with cells of the immune system that are present in the blood and lymph.

LYMPHOEDEMA

A condition in which fluid drainage from tissue is insufficient due to a dysfunctional or overloaded lymphatic system.

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Stacker, S., Achen, M., Jussila, L. et al. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2, 573–583 (2002). https://doi.org/10.1038/nrc863

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