Endoglin as a marker in cervical paragangliomas

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ENDOGLIN AS A MARKER IN CERVICAL PARAGANGLIOMAS Ne´lida Eleno, PhD,1 Annette Du¨wel, TBL,1 Angel Mun˜oz, MD,2 Jose´ Paz-Bouza, MD, PhD,3 Jose-Miguel Lo´pez-Novoa, PhD,1 Francisco Lozano, MD, PhD4 1

Instituto ‘‘Reina Sofı´a’’ de Investigacio´n Nefrolo´gica & Departamento de Fisiologı´a y Farmacologı´a, Universidad de Salamanca, Campus Miguel de Unamuno, Spain. E-mail: [email protected] 2 Servicio de Otorrinolaringologı´a, Hospital Clı´nico Universitario, Spain 3 Servicio de Anatomı´a Patolo´gica, Hospital Clı´nico Universitario, Spain 4 Departamento de Cirugı´a, Facultad de Medicina, Universidad de Salamanca & Servicio de Cirugı´a Vascular, Hospital Clı´nico Universitario, Salamanca, Spain Accepted 17 July 2009 Published online 13 October 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21248

Abstract: Background. Endoglin is expressed on endothelium and is implicated in the control of angiogenesis. This study compares the expression of endoglin with vascular endothelial growth factor (VEGF), commonly used as a marker for neoangiogenesis in cervical paragangliomas (CPG). Methods. The CPG were surgically obtained from 5 patients and compared with nontumoral lung obtained from patients subjected to pulmonary resection. Detection with specific antibodies was used to determine the expression of the proteins VEGF and endoglin. The expressions of hypoxia-inducible factor (HIF) and vascular cell adhesion molecule-1 (VCAM-1) were used to determine the degree of hypoxia and capillarization, respectively. Results. Endoglin is located at the plasma membrane of endothelial cells. The relative expression of endoglin is significantly higher in CPG respect to lung (p < .02), whereas that of VEGF is similar. Conclusion. Endoglin expression in CPG is significantly superior to that of VEGF and correlates with tumor C 2009 Wiley Periodicals, Inc. Head Neck vascularization. V 32: 737–743, 2010 Keywords: paraganglioma; endoglin; vascular growth factor (VEGF); angiogenesis; endothelium

Correspondence to: N. Eleno C 2009 Wiley Periodicals, Inc. V

Endoglin in Cervical Paragangliomas



are infrequent and usually benign neoplasias that derive from the neural crest. They are rare and can be found between the base of the cranium and the pelvic floor, most commonly affecting the cervical-cephalic area. Paragangliomas of the head and neck represent 0.6% of all tumors in the area and around 0.03% of all tumors.1 They are most commonly found in the carotid body, jugular bulb, and vagus nerve, in that order.2 Hypoxia, estrogens, and genetic factors contribute to the development of paragangliomas.3,4 It is known the presence of carotid body neoplasia in patients with chronic respiratory dysfunction/failure, as well as in normal people living at high altitude; in both cases, the frequency is higher in women.5 Moreover, the presence of a genetic autosomal dominant defect could trigger tumor development resulting in a 10% to 15% of cases in familiar paragangliomas.6 They are highly vascularized and the risk of their surgical extirpation frequently obligates to perform a preoperatory embolization.7 Endoglin (CD105) is a homodimeric transmembrane glycoprotein (180 kDa) predominantly expressed in endothelial cells.8 Endoglin is an

HEAD & NECK—DOI 10.1002/hed

June 2010


paragangliomas (CPG) surgically obtained from 5 patients, and we compare with the expression of vascular endothelial growth factor (VEGF), an angiogenic factor upregulated in paragangliomas.21 Recent reports suggest that elevated plasma levels of endoglin in patients with colorectal cancer or breast carcinoma correlate with poor prognosis.22 Moreover, we study the expression of hypoxia-inducible factor (HIF) as the primary angiogenic mediator liberated by the lack of oxygen occurring in the initiation of the neoangiogenesis pathway. The expression of vascular cell adhesion molecule 1 (VCAM-1) indicated as tumor vascularization. As a control, we used 5 surgically removed nontumorous parts of the lung, as this tissue shows the highest rate of endothelial cell abundance.23

accessory protein operating as nonsignaling receptor in the transforming growth factor (TGF)-b receptor complex. It is necessary for signaling transduction and modulates cellular responses to TGF-b in different types of cells.9–11 Endoglin plays a critical role in vascular development and function and participates in normal angiogenesis in adult.12 Thus, endoglin null (Eng/) murine embryos die of vascular defects at 10 to 10.5 days postcoitum.13– 15 Endoglin is the mutated gene for hereditary hemorrhagic telangiectasia type I (HHT-1), an autosomal dominant disorder characterized by multisystemic vascular dysplasia, and multiple arteriovenous shunts.16 Endoglin could have a key function in the regulation of neoangiogenesis crucial for tumor growth and progression. Studies of cultured endothelial cells propose that endoglin acts as a proangiogenic molecule.17 It is upregulated in proliferating endothelial cells and is strongly expressed in the neovasculature of a wide range of solid tumors.18 Besides, endoglin expression is weaker in nonmalignant adult tissue vessels, including preneoplasic lesions, than in tumor vessels.19,20 We assess the expression of endoglin, with diagnostic and prognostic purposes, in cervical

MATERIALS AND METHODS Tissue Samples. Five tumors were collected from patients of the Unit of Cardiovascular Surgery of the Hospital Clı´nico Universitario (Salamanca, Spain) from 2002 to 2005. Tumors were numbered from 1 to 5 as indicated in Table 1.

Table 1. Individual data of the 5 cases of cervical paraganglioma (CPG) under study. Characteristic

Case 1

Case 2

Case 3

Case 4

Case 5

Age, y/sex Localization Clinical picture Tumor Symptoms Familiar history Diagnosis CT MRI DSA Pentetreotide Characteristics Single Multicentric Malignant Functional Size, cm Surgery Embolization No. of surgical operations Years Postoperative sequellae Cranial nerve CVA Death

42/male Carotid

69/female Carotid

38/female Carotid

56/male Vagal

70/male Carotid

þ þ 



þ þ 

þ þ 

þ þ ND þ

þ ND þ þ

þ ND þ þ

þ ND þ þ

þ þ ND þ

 þ1† þ  5.1

þ    3.5

 þ1‡   3.6

þ    4.3

þ    5.2

ND 2 1997/02*

ND 1 2002

ND 1 2003

þ 1 2003

þ 1 2005






Abbreviations: DSA, digital subtraction angiography; CVA, cerebrovascular accident; ND, not done. *Carotid body tumor contralateral
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