Analysis of neovasculature in uveal melanoma by targeting the TGFbeta-binding receptor endoglin: is there prognostic relevance of proliferating endothelium?
BACKGROUND
Endoglin/CD105 is a transmembrane regulatory receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells (ECs) in culture and on angiogenic blood vessels in vivo. Endoglin has been associated with angiogenesis and prognosis in several malignancies. Although microvascular structure has been characterized by a variety of different other endothelial markers so far, there is no consensus on the prognostic value of microvessel quantification in uveal melanoma due to differences in tissue pretreatment, variability in the reactivity of endothelial cell markers, blood vessel counting methods, and vasculogenic mimicry by melanoma cells expressing endothelial cell markers. The aim of this study was to investigate the expression pattern of endoglin and to evaluate whether proliferative activity of ECs determines the clinical prognosis of uveal melanoma.


METHODS
Paraffin sections from 35 clinicopathologically well-characterized cases of primary uveal melanomas were stained for Ki-67, von Willebrand factor (vWF) and endoglin. In 16 cases, metastatic disease led to death. The mean follow-up of the nonmetastasized cases was 10.6 (9-13) years. The immunohistological specimens were evaluated by three independent observers who were masked to the follow-up of patients. Statistical analyzes included Kaplan-Meier survival curves and the fitting of log-rank and Wilcoxon test models.


RESULTS
Immunohistochemistry with vWF confirmed that all examined specimens were vascularized. Expression of Ki-67 could be found in 26 (74%) of the samples. Moderate to high expression of endoglin was found in 13 cases (37%). Kaplan-Meier analysis showed a significant association (p<0.001) between an enhanced endoglin expression and death due to metastatic uveal melanoma.


CONCLUSIONS
The study demonstrates for the first time that the expression of endoglin can be used as a specific marker for angiogenesis in uveal melanomas. Thus, differentiation between the quiescent and proliferating ECs enables the location and characterization of hot spots of angiogenesis in melanomas. The data suggest not only a prognostic relevance in individual patients but promise applications in assessing the efficacy of antiangiogenic agents.
Ziemssen
Focke
F
Department of Ophthalmology I, Eberhard-Karls University Tuebingen, Tuebingen, Germany.
Wegner
Rayime
R
Wegner
Jürgen
J
Tatar
Olcay
O
Süsskind
Daniela
D
Gelisken
Faik
F
Rohrbach
Martin
M
Bartz-Schmidt
Karl U
KU
Grisanti
Salvatore
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000098:blood supply* / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D015588:Observer Variation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014604:Uveal Neoplasms / Q000098:blood supply* / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism
D015703:Antigens, CD; D014408:Biomarkers, Tumor; C064206:ENG protein, human; D000071063:Endoglin; D019394:Ki-67 Antigen; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor