Prox 1, VEGF-C and VEGFR3 expression during cervical neoplasia progression as evidence of an early lymphangiogenic switch.

Dec 2012

Cimpean AM, Mazuru V, Saptefrati L, Ceausu R, Raica M.

Source

Department of Histology, Angiogenesis Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania. ancacimpean1972@yahoo.com.

Abstract

Prox1 is a key regulator of lymphatic endothelial cell commitment during embryonic development. No correlations between Prox1 and VEGF-C/VEGFR3 expression in cervical cancer has been done until now. The aim of the present study was to evaluate the peculiarities of Prox1, VEGF-C and VEGFR3 expression during uterine cervix neoplasia progression. Material and methods. One hundred and four specimens taken from women with macroscopically detectable lesions were classified by histopathology and analyzed by immunohistochemistry for Prox1, VEGFR3 and VEGF-C expression. 

Results. 

The presence of Prox1 nuclear expression was detected starting from CIN2 and CIN3 lesions to microinvasive carcinoma, in the nuclei of lymphatic and venous endothelial cells and scattered stromal cells. All Prox1 positivelymphatic vessels were positive for VEGFR3. A significant correlation was found between expression of VEGF-C in tumor cells and nuclear density of Prox1 positive lymphatic cells (p=0.044). 

Conclusion. 

The commitment of Prox1 positive cells through a lymphatic lineage is an early event for cervical neoplastic progression, being present starting with intraepithelial cervical lesions, and is strongly associated with VEGFR3 and VEGF-C expression. These findings suggest an early active lymphangiogenesis during cervical neoplasia progression and explain, in part, the early presence of lymph node metastasis in cervical cancer. By the detection of Prox1 expression in lymphatic and venous endothelial cells, and also in stromal cells, it has been suggested that there are at least three different mechanism of lymph vessel development during cervical neoplasia progression.

Histology and Histopathology

see also:

Lymphedema Gene CCBE1

Lymphedema Gene FLT4

Lymphedema Gene FOXC2

Lymphedema Gene GATA2

Lymphedema Gene GJC2

Lymphedema Gene KIF11

Lymphedema Gene SOX18

Lymphedema Gene VEGFC

A new classification system for primary lymphatic dysplasias based on phenotype.

May 2010

Connell F, Brice G, Jeffery S, Keeley V, Mortimer P, Mansour S.

Source

Medical Genetics Unit, Clinical Developmental Sciences, St George's University of London, Cranmer Terrace, London SW170RE, UK.

Abstract

Traditional classification systems for lymphoedema are of limited use for the diagnosis of specific forms of primary lymphoedema. The understanding of primary lymphoedema has been impeded by confusing terminology and a tendency to simply divide patients into three categories based on the age of onset: lymphoedema congenita manifests at or shortly after birth, lymphoedema praecox is apparent before the age of 35 years and lymphoedema tarda manifests thereafter. The clinical presentation in the spectrum of primary lymphoedema disorders is very variable; the phenotypes of primary lymphoedema conditions vary in the age of onset, site of the oedema, inheritance patterns, associated features and genetic causes. Different inheritance patterns are recognised and there are numerous associated anomalies. Some subgroups, such as Milroy disease and Lymphoedema distichiasis, are well characterised, but others are not. A new clinical classification for primary lymphoedema has been developed as a diagnostic algorithm. Its use is demonstrated on 333 probands referred to our lymphoedema clinic. Grouping patients by accurate phenotyping facilitates molecular investigations, understanding of inheritance patterns, and the natural history of different types of primary lymphoedema. Descriptions of the diagnostic categories, some of which have not been previously clearly defined as distinct clinical entities, are illustrated by clinical cases.

Wiley Online Library

Pr08 lymphatic malformations and the molecular basis of lymphangiogenesis. Options

Pr08 lymphatic malformations and the molecular basis of lymphangiogenesis.

Options

ANZ J Surg. 2007 May

Ch'ng S, Tan ST. Wellington Regional Plastic Unit, Hutt Hospital, Wellington, New Zealand.
This paper reviews the clinical features of lymphatic malformations and the molecular basis of embryonic lymphangiogenesis.

Lymphatic malformations are classified as microcystic, macrocystic, or combined. Most commonly found in the axilla/chest and cervicofacial region, they can be localised or diffuse. The commonest complications are intralesional bleeding and infection. Other significant complications are due mainly to their mass effect on nearby anatomic structures including the airway and eyeball, and soft tissue and skeletal overgrowth including macrocheilia, macroglossia, macrotia, macromala and mandibular prognathism, resulting in functional problems in feeding, speech, occlusion, oral hygiene, and disfigurement.

The characteristic radiological finding of a LM on gadolinium-enhanced T1-weighted MRI is a low-density lesion with septation or rim enhancement. Histologically, LMs are cystic lesions that contain eosinophilic proteinaceous fluid whose walls are composed of smooth and skeletal muscle fibres, collagen and lymphocytes. Management options range from observation, comfort cares, empirical antibiotic treatment for LM cellulitis to sclerotherapy, surgical excision and Nd:YAG laser for selected cases.

Lymphangiogenesis is believed to occur in four sequential but overlapping stages: lymphatic endothelial cell competence, bias and specification, and finally lymphatic vessel terminal differentiation and maturation. Multiple genes are involved in this process including Lyve1, Nrp2, podoplanin, Prox1, VEGFR3, VEGFC and Ang2. Developmental defects during embryonic lymphangiogenesis result in lymphatic malformations.

PMID: 17490238 [PubMed - in process]