Role of lymphangiogenic factors in tumor metastasis

doi:10.1016/j.bbcan.2003.07.003

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

Volume 1654, Issue 1, 4 March 2004, Pages 3-12

https://doi.org/10.1016/j.bbcan.2003.07.003 Get rights and content

Abstract

Nearly four centuries after the discovery of lymphatic vessels, the molecular mechanisms underlying their development are beginning to be elucidated. Vascular endothelial growth factor C (VEGF-C) and VEGF-D, via signaling through VEGFR-3, appear to be essential for lymphatic vessel growth. Observations from clinicopathological studies have suggested that lymphatic vessels serve as the primary route for the metastatic spread of tumor cells to regional lymph nodes. Recent studies in animal models have provided convincing evidence that tumor lymphangiogenesis facilitates lymphatic metastasis. However, it is not clear how tumor-associated lymphangiogenesis is regulated, and little is known about how tumor cells escape from the primary tumor and gain entry into the lymphatics. This review examines some of these issues and provides a brief summary of the recent developments in this field of research.

Introduction

The major roles of the lymphatic system include the maintenance of tissue fluid homeostasis and transport of macromolecules and immune cells back into the blood circulation via the collecting lymphatic vessels and the thoracic duct. Two theories about the development of the lymphatic vessel system were proposed at the beginning of the last century; these were the venous origin of the lymphatic vessels [1] and de novo formation of primary lymph sacs in the mesenchyme [2]. Supporting evidence has been published for both views [3], [4], suggesting that the development of the lymphatic system may require both mechanisms. Studies during the last few years have provided significant insights into the molecular mechanisms underlying the development of lymphatic vessels and the role of lymphangiogenesis in health and disease [5]. The achievement owes largely to the discovery of the key lymphatic growth factors (vascular endothelial growth factor C (VEGF-C) and VEGF-D) and their receptor VEGFR-3, and more recently of several specific molecular markers to indentify lymphatic vessels. Such developments have opened up a new research frontier, extending the tumor angiogenesis field to studies of tumor lymphangiogenesis and metastasis.

Section snippets

Molecular regulation of lymphatic vessel development

The identification of specific lymphatic markers has greatly facilitated studies of lymphangiogenesis. VEGFR-3 is one of the first lymphatic markers identified. During the murine development, VEGFR-3 was initially expressed in endothelial cells (ECs) of developing blood vessels, but its expression becomes restricted to lymphatic endothelial cells (LECs) after midgestation and persists in adult lymphatic vessels [6]. Expression of VEGFR-3 has also been shown in adult fenestrated blood vessel

Lymphangiogenesis promotes lymphatic metastasis

Accumulating data from clinicopathological studies suggest that spread to of cancer cells regional lymph nodes is an early event for many solid tumors, and lymphatic vessels serve as the primary route for this spread [46]. However, until recently the issue regarding the existence of lymphatic vessels in human cancers has been controversial. The availability of lymphatic markers has helped to clarify the situation. These markers have been used alone or in combination to study the presence of

Lymphatic metastasis: a passive or an active event?

Tumor cells or emboli have to overcome a series of barriers to establish metastases in distant organs. Multiple molecular and cellular responses initiated by a combination of various stimuli may be required for the metastatic event. These sequential processes are thought to include induction of angiogenesis and/or lymphangiogenesis, detachment from surrounding tumor cell mass and access to blood or lymphatic vessels, survival in the circulation, random or specific arrest in the microvasculature

Concluding remarks

Recent studies have demonstrated that tumor lymphangiogenesis does occur in some human cancers, and tumor-associated lymphatics are necessary for lymph node metastasis. In animal models, inhibition of lymphangiogenesis by blocking VEGFR-3 signaling or by neutralization of chemokines such as SLC/CCL21 has been shown to suppress lymph node metastasis. This implies the therapeutic potential of targeting proliferating LECs or their paracrine interactions with the tumor cells. However, it remains to

Acknowledgments

We thank Alun Parsons for the review of the language. This study was supported by grants from the Ida Montini Foundation, the Ella and Georg Ehrnrooth Foundation, the Finnish Cultural Foundation, the Foundation of the Finnish Cancer Institute, the Paulo Foundation, the Finnish Academy of Sciences and the Novo Nordisk Foundation, Helsinki University Hospital Funds, The Human Frontier Science Foundation, the European Union (Angionet) and National Institutes of Health.

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ReviewRole of lymphangiogenic factors in tumor metastasis

Abstract

Introduction

Section snippets

Molecular regulation of lymphatic vessel development

Lymphangiogenesis promotes lymphatic metastasis

Lymphatic metastasis: a passive or an active event?

Concluding remarks

Acknowledgments

Cell

Cancer Cells

Am. J. Pathol.

Am. J. Pathol.

J. Biol. Chem.

Trends Immunol.

Am. J. Pathol.

Dev. Biol.

J. Biol. Chem.

Am. J. Pathol.

Dev. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biomech.

Am. J. Pathol.

Surgery

Neoplasia

Gynecol. Oncol.

Eur. J. Cancer

On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig

Am. J. Anat.

The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica)

Am. J. Anat.

Lymphangioblasts in the avian wing bud

Dev. Dyn.

Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development

Proc. Natl. Acad. Sci. U. S. A.

VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues

FASEB J.

Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma

Cancer Res.

Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis

Am. J. Pathol.

Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi's sarcoma tumor cells

Lab. Invest.

Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages

J. Exp. Med.

LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan

J. Cell Biol.

LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis

Cancer Res.

An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype

EMBO J.

Complexus adhaerentes, a new group of desmoplakin-containing junctions in endothelial cells: the syndesmos connecting retothelial cells of lymph nodes

Eur. J. Cell Biol.

Enzyme-histochemical identification of lymphatic vessels by light and backscattered image scanning electron microscopy

Stain Technol.

Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells

J. Exp. Med.

Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium

J. Exp. Med.

Hyperplasia of lymphatic vessels in VEGF-C transgenic mice

Science

Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice

EMBO J.

A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases

EMBO J.

Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4

Proc. Natl. Acad. Sci. U. S. A.

Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)

Proc. Natl. Acad. Sci. U. S. A.

Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3

Nat. Med.

Proteolytic processing regulates receptor specificity and activity of VEGF-C

EMBO J.

Vascular endothelial growth factor C induces angiogenesis in vivo

Proc. Natl. Acad. Sci. U. S. A.

c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro

Proc. Natl. Acad. Sci. U. S. A.

Cardiovascular failure in mouse embryos deficient in VEGF receptor-3

Science

Review
Role of lymphangiogenic factors in tumor metastasis