Regulation of lymphatic vascular morphogenesis: Implications for pathological - tumor lymphangiogenesis.

Feb 2013

Martinez-Corral I, Makinen T.

Source

Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Abstract

Lymphatic vasculature forms the second part of our circulatory system that plays a critical role in tissue fluid homeostasis. Failure of the lymphatic system can lead to excessive accumulation of fluid within the tissue, a condition called lymphedema. Lymphatic dysfunction has also been implicated in cancer metastasis as well as pathogenesis of obesity, atherosclerosis and cardiovascular disease. Since the identification of the first lymphatic marker VEGFR-3 and growth factor VEGF-C almost 20 years ago, a great progress has been made in understanding the mechanisms of lymphangiogenesis. This has been achieved largely through characterization of animal models with specific lymphatic defects and identification of genes causative of human hereditary lymphedema syndromes. In this review we will summarize the current understanding of the regulation of lymphatic vascular morphogenesis, focusing on mechanisms that have been implicated in both developmental and pathological (tumor) lymphangiogenesis.

Elsevier

Emilin1 Deficiency Causes Structural and Functional Defects of Lymphatic Vasculature

Emilin1 Deficiency Causes Structural and Functional Defects of Lymphatic Vasculature
Mol Cell Biol. 2008 Apr 14

Danussi C, Spessotto P, Petrucco A, Wassermann B, Sabatelli P, Montesi M, Doliana R, Bressan GM, Colombatti A.
Division of Experimental Oncology 2, Department of Molecular Oncology and Translational Research, CRO-IRCCS, Aviano, Pordenone, Italy; IGM-CNR, Unit of Bologna c/o IOR, Bologna, Italy; Mouse Genetics Laboratory, Department of Histology Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy; Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy; and MATI Center of Excellence, University of Udine, Udine, Italy.

Lymphatic vasculature function critically depends on extracellular matrix (ECM) and on its connections with lymphatic endothelial cells (LECs). However, the composition and the architecture of ECM have been poorly taken into consideration when studying the biology and the pathology of the lymphatic system. EMILIN1, an elastic microfibril associated protein, is highly expressed by LECs in vitro and co-localizes with lymphatic vessels in several mouse tissues. A comparative study between wild-type and Emilin1(-/-) mice highlighted that Emilin1 deficiency in both CD1 and C57BL/6 background results in hyperplasia, enlargement and frequently irregular pattern of superficial and visceral lymphatic vessels and in a significant reduction of anchoring filaments. Emilin1-deficient mice also develop larger lymphangiomas than wild-type mice. Lymphatic vascular morphological alterations are accompanied by functional defects such as mild lymphedema, highly significant drop in lymph drainage, and enhanced lymph leakage. Our findings demonstrate that EMILIN1 is involved in the regulation of the growth and in the maintenance of the integrity of lymphatic vessels, a fundamental requirement for an efficient function. The phenotype displayed by Emilin1(-/-) mice is the first abnormal lymphatic phenotype associated with the deficiency of an ECM protein and identifies EMILIN1 as a novel local regulator of lymphangiogenesis.

Molecular and Cellular Biology

Molecular Biology and Pathology of Lymphangiogenesis

Molecular Biology and Pathology of Lymphangiogenesis

Karpanen T, Alitalo K.
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, FI-00014 Helsinki, Finland t.karpanen@niob.knaw.nl.

Abstract

The lymphatic vasculature is essential for the maintenance of tissue fluid balance, immune surveillance, and adsorption fatty acids in the gut. The lymphatic vessels are also crucially involved in the pathogenesis of diseases such as tumor metastasis, lymphedema, and various inflammatory conditions. Attempts to control or treat these diseases have drawn a lot of interest to lymphatic vascular research during the past few years. Recently, several markers specific for lymphatic endothelium and models for lymphatic vascular research have been characterized, enabling great technical progress in lymphatic vascular biology, and many critical regulators of lymphatic vessel growth have been identified. Despite these significant achievements, our understanding of the lymphatic vessel development and pathogenesis is still rather limited. Several key questions remain to be resolved, including the relative contributions of different pathways targeting lymphatic vasculature, the molecular and cellular processes of lymphatic maturation, and the detailed mechanisms of tumor metastasis via the lymphatic system. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 3 is January 24, 2008. Please see article for revised estimates.

PMID: 18039141 [PubMed - as supplied by publisher]