Trends in Immunology
Volume 25, Issue 7, 1 July 2004, Pages 387-395
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Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation

https://doi.org/10.1016/j.it.2004.05.003Get rights and content

Abstract

The lymphatic vascular system is important for immune surveillance, tissue fluid homeostasis and fat absorption, and is involved in many pathological processes, including tumor metastasis and lymphedema. The recent success in the isolation of lymphatic endothelial cells has shed light on their molecular characteristics. Lymphatic commitment and growth during embryonic development is dependent on the activities of the homeodomain transcription factor Prox-1 and vascular endothelial growth factor-C (VEGF-C). VEGF-C and VEGF-D are involved in adult inflammation-associated lymphangiogenesis, wound healing and tumor metastasis. Administration of lymphangiogenic growth factors or their antagonists provides the possibility of targeting lymphatic vessels in human disease.

Section snippets

Lymphatic commitment, sprouting and growth

The development of the lymphatic vasculature during embryogenesis lags behind that of the blood vessels, suggesting that these processes are regulated by different signals [2]. A century ago, Florence Sabin had already proposed a widely accepted theory concerning the venous origin of the lymphatic vasculature [3]. Recent studies of mice deficient in the homeobox transcription factor Prox-1 or vascular endothelial growth factor C (VEGF-C) support this model 4, 5 (Figure 2). Prox-1 is first

Molecular regulation of lymphangiogenesis

VEGFR-3 was one of the first LEC-specific cell surface molecules to be characterized. However, before mid-gestation, VEGFR-3 is also expressed in BECs, and Vegfr3−/− embryos die at E9.5 due to abnormal remodeling of the primary vascular plexus [8]. In adults, the expression of VEGFR-3 becomes confined to the lymphatic endothelium [9]. In addition, fenestrated capillaries and veins in certain endocrine organs, as well as monocytes, macrophages and some dendritic cells (DCs), continue to express

Characteristics of LECs

Although the blood vascular endothelium and its tissue-specific heterogeneity have been the subject of several studies, similar studies of the lymphatic endothelium have been hampered by difficulties in isolating LECs from different tissues. Recently, LECs have been purified to homogeneity from the skin microvasculature, using immunomagnetic isolation based on LEC surface markers, such as VEGFR-3, podoplanin or LYVE-1 24, 35, 36, 37, 38, thus enabling more detailed studies of LECs (Figure 3).

Dysfunction of lymphatic vessels

In lymphedema, the transport capacity of lymphatic vessels is decreased, and fluid accumulates in tissues causing chronic and disabling swelling, tissue fibrosis, adipose degeneration, poor immune function and susceptibility to infections, as well as impaired wound healing [45]. Primary lymphedemas are rare developmental disorders, which can manifest at birth (Milroy's disease) or at the onset of puberty (Meige's disease) [46]. It has been estimated that 1:6000 of newborns develop primary

Lymphangiogenesis promotes tumor metastasis

The capacity of malignant tumors to metastasize presents a difficult problem for cancer treatment. Lymphatic vessels provide one of the main routes for tumor metastasis, especially for tumors of the breast, lung and gastrointestinal tract, which frequently colonize draining regional lymph nodes. Compared to the blood vasculature, little is known about the biology of the lymphatic vessels in tumors, the regulation of tumor lymphangiogenesis or the mechanisms that determine the interactions of

Inflammation stimulates angiogenesis and lymphangiogenesis

In adults, wound healing, cancer and inflammation are pathological conditions associated with rapid neovascularization. There is increasing evidence that inflammatory cells have an important role in pathological angiogenesis and lymphangiogenesis [76]. Activated leukocytes secrete several cytokines and other regulatory proteins, such as VEGF. The expression of VEGF is induced by hypoxia, which has an important role in tumor angiogenesis, and by proinflammatory cytokines 77, 78, 79. VEGF is

Concluding remarks

Since the discovery of the first LEC-specific molecules less than a decade ago, tremendous progress has been made in understanding the function and development of lymphatic vessels. Prox-1, VEGF-C, VEGF-D and VEGFR-3 are central regulators of lymphatic development. Prox-1 is a determinant of the commitment of LECs in the embryonic cardinal veins; however, it is not known what turns on the polarized Prox-1 expression in this subpopulation of venous ECs. Vegfc−/− embryos do not have an obviously

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