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Transforming Growth Factor-ß Binding Receptor Endoglin (CD105) Expression in Esophageal Cancer and in Adjacent Nontumorous Esophagus as Prognostic Predictor of Recurrence

¹ Division of Internal Medicine, Department of Clinical Physiopathology, University of Turin, Turin, Italy
² Third Division of General and Esophageal Surgery, Department of Clinical Physiopathology, University of Turin, Turin, Italy
³ Department of Gastroenterology and Clinical Nutrition, S. Giovanni Battista Hospital, Turin, Italy
⁴ Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy

Correspondence: Address correspondence and reprint requests to: Graziella Bellone, PhD; E-mail: graziella.bellone{at}unito.it

Background: We hypothesized that the potent neovascularization marker endoglin (CD105), by differentially highlighting a subset of microvessels (MV) in esophageal cancer (EC), could provide better prognostic/therapeutic information than the panendothelial marker CD34, which also highlights MV.

Methods: Endoglin messenger ribonucleic acid (mRNA) expression in normal, malignant, and adjacent nontumorous esophagus tissue was quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). Sections of formalin-fixed, paraffin-embedded tissues were analyzed immunohistochemically for CD105 and CD34. MV density was counted following a standard protocol. Circulating soluble endoglin levels were determined in patient and control sera, and compared with clinical outcome.

Results: CD105 mRNA was upregulated by a median factor of 2.89 in ECs versus controls. In 28% of patients, CD105 mRNA was upregulated by a median factor of 2.65 in adjacent non-tumorous versus normal tissue. In tumor tissues, CD105 was stained negatively or positively only in a subset of MV. CD34 always showed positive extensive MV staining. In adjacent nontumorous esophagus, CD105 rarely showed diffuse MV staining, while CD34 stained blood-vessel endothelial cells in all non-neoplastic tissue. CD105 expression was high in residual highly dysplastic Barrett’s-type mucosa associated with some adenocarcinomas. No statistically significant difference in endoglin serum levels appeared between patients and normal subjects. Correlation with clinicopathological data showed higher intra-tumor MV-CD105+ scores at more-advanced clinical stages. High-scoring MV-CD105+ patients had significantly shorter disease-free and overall survival; MV-CD34+ density was not survival related. Diffuse CD105 expression in adjacent nontumorous esophagus predicted poorer disease-free and overall survival.

Conclusions: Our findings could help identify EC patients who may benefit from targeted anti-angiogenic therapies.

Key Words: Endoglin • CD34 • Tumor angiogenesis • Microvessel density • Esophageal cancer