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

Cervical lymph nodes

Cervical lymph nodes

Eur J Radiol. 2008 Mar 10

Mack MG, Rieger J, Baghi M, Bisdas S, Vogl TJ.
Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.

The lymph node staging is a very important prognostic parameter for patients with presenting with head neck cancer and is influencing the selection of the different therapeutic strategies including surgery, chemotherapy, radiotherapy or a combination of them. The accuracy of imaging techniques, such as US, MR imaging, and CT, depends on the appropriateness of radiological criteria used for diagnosing lymph node metastases. Size of nodes and evidence of necrosis are still the most important radiological criteria. However, the size shows great variability. A spherical lymph node larger than 10mm is an indicator for a malignant node, whereas an oval shape and/or a fatty hilus are more benign signs. But there are many limitations and different cut offs published in the literature, indicating that the size of a lymph node is not a reliable criteria for the assessment of lymph nodes in the head and neck region. Today new high-resolution MRI sequences and the development of specific contrast agents are offering new possibilities in the diagnostic work-up of head and neck lymph nodes. Ultrasmall superparamagnetic iron oxide particles (USPIO's) are resulting after intravenous application in a reduction of the T2 relaxation time. This is causing a signal decrease on T2-weighted MR images in benign lymph nodes after administration of USPIO's, whereas malignant lymph nodes do not show a significant signal decrease. Some clinical studies presented already very promising results. Based on the fact, that the size evaluation of lymph nodes in the head and neck has not changed during the last decade, this paper will mainly focus on MRI with new contrast agents and new techniques as diffusion weighted imaging (DWI).

PMID: 18337039 [PubMed - as supplied by publisher]

Lymphangiogenesis in development and disease

Lymphangiogenesis in development and disease

Thrombosis and Haemostasis 2007

Ruediger Liersch1, Michael Detmar2
1Department of Medicine, Hematology and Oncology, University Hospital Muenster, Muenster, Germany; 2Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland

Summary

The lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells.The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutation- al inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

Keywords
Lymphatic endothelium, lymphangiogenesis, lymphedema, inflammation, cancer metastasis

Schattauer

Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin

Overexpression of VEGF-C causes transient lymphatic hyperplasia (lymphedema) but not increased lymphangiogenesis in regenerating skin.

Goldman J, Le TX, Skobe M, Swartz MA. Biomedical Engineering Department, Northwestern University, Evanston, Ill, USA.

Correspondence to Dr Melody A. Swartz, Assistant Professor, Institute for Biological Engineering and Biotechnology, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. E-mail melody.swartz@epfl.ch

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis and holds potential for lymphangiogenic therapy in diseases lacking adequate lymphatic drainage. However, the ability of VEGF-C to enhance sustainable, functional lymphatic growth in adult tissues remains unclear. To address this, we evaluated VEGF-C overexpression in adult lymphangiogenesis in regenerating skin. We used a model of mouse tail skin regeneration incorporating a suspension of either VEGF-C overexpressing tumor cells, which provide a continuous supplement of excess VEGF-C to the natural regenerating environment for more than 25 days, or otherwise identical control- transfected tumor cells. We found that excess VEGF-C did not enhance the rate of lymphatic endothelial cell (LEC) migration, the density of lymphatic vessels, or the rate of functionality -- even though lymphatic hyperplasia was present early on. Furthermore, the hyperplasia disappeared when VEGF-C levels diminished, which occurred after 25 days, rendering the lymphatics indistinguishable from those in control groups. In vitro, we showed that whereas cell-derived VEGF- C could induce chemoattraction of LECs across a membrane (which involves amoeboid-like transmigration), it did not increase LEC chemoinvasion within a 3-dimensional fibrin matrix (which requires proteolytic migration). These results suggest that whereas excess VEGF- C may enhance early LEC proliferation and cause lymphatic vessel hyperplasia, it does not augment the physiological rate of migration or functionality, and by itself cannot sustain any lasting effects on lymphatic size, density, or organization in regenerating adult skin.

AHA Journals

Definitive percutaneous treatment of lymphatic malformations of the trunk and extremities

Definitive percutaneous treatment of lymphatic malformations of the trunk and extremities

J Pediatr Surg. 2008 Jan

Shiels WE 2nd, Kenney BD, Caniano DA, Besner GE.
Department of Radiology, Nationwide Children's Hospital, The Ohio State University Medical Center, Columbus, OH 43205, USA. william.shiels@nationwidechildrens.org

PURPOSE: The aim of this study is to investigate a new treatment regimen for macrocystic and microcystic lymphatic malformations (LMs) of the trunk and extremities.

METHODS: Sixteen patients (aged 2 months-22 years) underwent percutaneous treatment for LM of the trunk and extremities from 2002 to 2007. The LM involved the arm, leg, axilla, chest, abdomen, scrotum, and penis. Eleven patients underwent primary treatment of LM; 5 were treated for recurrence after prior operative resection. Macrocysts (>or=1 cm) were treated with dual-drug chemoablation (sequential intracystic sodium tetradecyl sulfate and ethanol); doxycycline was used for microcysts. Macrocysts and microcysts were treated after complete cyst aspiration using sonographic guidance. Twenty-four macrocysts and 103 microcysts were treated. The goal of treatment was complete cyst ablation documented by sonography or magnetic resonance imaging.

RESULTS: The mean number of treatments was 1.7 per patient; the mean number of treatments for macrocysts was 1.3 and for microcysts was 1.7. Ablation efficacy was 100% (127/127 cysts). Treatments included massive intraperitoneal cysts and cysts surrounding the adventitia of the brachial artery and brachial nerve. Infection occurred in 2 (13%) of 16 patients. No patient experienced postprocedural pain, skin necrosis, neuropathy, bowel obstruction, skin retraction, or myoglobinuria.

CONCLUSIONS: Percutaneous sclerotherapy provides effective treatment for macrocystic and microcystic LM as primary treatment or for recurrence after surgical resection.

Elsevier

Congenital vascular malformations: general diagnostic principles.

Congenital vascular malformations: general diagnostic principles.
Phlebology. 2007

Lee BB, Laredo J, Lee SJ, Huh SH, Joe JH, Neville R.
Department of Surgery, Georgetown University, Washington, DC, USA. bblee38@comcast.net

Venous malformation (VM) is the most common congenital vascular malformation (CVM), which usually presents as a single lesion in the majority of cases. It also presents as a mixed lesion combined with other CVMs (e.g. lymphatic malformation and arteriovenous malformation [AVM]). Therefore, the diagnosis of VM should include an appropriate work-up, to not only confirm and characterize the VM as either extratruncular or truncular but also to diagnose or exclude the presence of other CVMs. The diagnosis of VM can be made safely using non-invasive to minimally invasive studies, which can also distinguish VM from infantile haemangioma. Invasive studies, such as venography and arteriography, are generally reserved for therapeutic planning and diagnosis of more virulent CVMs (e.g. AVM). The work-up of VM should include a complete assessment of the extent and severity of the primary VM lesion. In addition, its embryologic origin, as well as its haemodynamic characteristics and secondary effects should also be determined.

PMID: 18274332 [PubMed - in process]

Laser excision of multiple esophageal lymphangiomas: A case report and review of the literature.

Laser excision of multiple esophageal lymphangiomas: A case report and review of the literature.
Auris Nasus Larynx. 2008 Feb 1

Best SR, Coelho DH, Ahrens WA, Atez G, Sasaki CT.
Yale University School of Medicine Division of Otolaryngology, Head & Neck Surgery, New Haven, CT, USA.

Lymphangiomas of the gastrointestinal tract are rare and benign submucosal tumors. We present the first case of multiple lymphangiomas in the cervical esophagus and only the 15th case of an esophageal lymphangioma. A 63-year-old male presented to our clinic with two years of dysphagia and an esophageal mass noted on MRI. A barium swallow confirmed a polypoid mass of the upper esophagus with operative findings of two smooth pedunculated lymphangiomas occupying the entire lumen of the esophagus. Previous reports have documented successful surgical intervention through open or endoscopic techniques, whereas the favorable location of the tumors in this case allowed for the first successful excision utilizing a CO(2) laser. We demonstrate here that esophageal laser surgery can provide an accurate, complete, and minimally invasive excision technique for lymphangiomas of the upper digestive tract with minimal morbidity for the patient. A complete review of all published cases is presented, with a focus on the clinical presentation and surgical treatment of this disease.

PMID: 18243618 [PubMed - as supplied by publisher]