Elsevier

Journal of Biotechnology

Volume 124, Issue 1, 25 June 2006, Pages 224-241
Journal of Biotechnology

Review
Tumor-induced lymphangiogenesis: A target for cancer therapy?

https://doi.org/10.1016/j.jbiotec.2006.01.007Get rights and content

Abstract

Recent advances in understanding the biology of lymphangiogenesis, the new growth of lymphatic vessels, have cast new light on the molecular basis of metastasis to regional lymph nodes. The receptor tyrosine kinase VEGFR-3 is virtually exclusively expressed on lymphatic but not blood endothelium in the adult, and activation of VEGFR-3 by its ligands VEGF-C and VEGF-D is sufficient to induce lymphangiogenesis. Correlative studies with human tumors and functional studies using animal tumor models show that increased levels of VEGF-C or VEGF-D in tumors lead to enhanced numbers of lymphatic vessels in the vicinity of tumors, which in turn promotes metastasis to regional lymph nodes by providing a greater number of entry sites into the lymphatic system for invading tumor cells. These findings have prompted studies to investigate whether inhibitors of VEGFR-3 activation might represent novel therapeutic agents for the suppression of metastasis. However, a number of points regarding the therapeutic potential of anti-lymphangiogenic treatments in the context of cancer remain to be addressed. The spectrum and relative importance of molecules that induce lymphangiogenesis and the regulation of their expression during tumor progression, the reversibility of tumor-induced lymphangiogenesis, and possible side-effects of anti-lymphangiogenesis-based therapies all need to be investigated. Most importantly, the extent to which lymph node metastases contribute to the formation of metastases in other organs remains to be elucidated. These aspects are the focus of this review, and their investigation should serve as a roadmap to possible translational application.

Section snippets

Introduction to the lymphatic system and its molecular biology

Lymphatic capillaries are blind-ended vessels which drain lymphatic fluid from peripheral tissues into larger collecting ducts which empty into the venous system, in the main via the thoracic duct. The lymphatic system plays a vital role in maintaining homeostasis, returning to the circulatory system around 10% of the volume of interstitial fluid escaping from tissue capillary beds (the physiology of the lymphatic system is thoroughly reviewed in Guyton and Hall, 1996). Equally importantly, it

The lymphatics and cancer metastasis

The majority of cancer patients die as a result of metastatic dissemination of their tumor, and a key turning point in the course of cancer progression is thus the development of metastatic potential. In this regard, metastasis to regional lymph nodes is often the first indication that a tumor has progressed to metastatic competence, and regional lymph node status is highly clinically significant for the prognostic evaluation of a broad spectrum of tumor types (reviewed in Sleeman, 2000). These

Tumor-induced lymphangiogenesis: a possible therapeutic target for suppressing metastasis

Our current understanding of the importance of tumor-induced lymphangiogenesis for the formation of lymph node metastases suggests that by blocking the activity of key molecules such as VEGFR-3 it should be possible to suppress the onset of metastasis. Although it is unlikely that the growth of pre-existing metastases would be affected, the inhibition of tumor-induced lymphangiogenesis should reduce the onset of new metastases following diagnosis of cancer and its subsequent therapy.

Conclusions

The rapid rise in research into the regulation of lymphangiogenesis in recent years has dramatically increased our understanding of the role the lymphatic vasculature in a number of physiological and pathological processes, including tumor metastasis. We now have the clear prospect of being able to apply this knowledge translationally to the suppression of the onset of the deadliest aspect of cancer, namely metastasis. Despite this promise, considerable work still needs to be done in order to

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