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Tumor Origin of Endothelial Cells in Human Neuroblastoma

Annalisa Pezzolo, Federica Parodi, Maria Valeria Corrias, Roberta Cinti, Claudio Gambini, Vito Pistoia

From the Laboratories of Oncology and Pathology, G. Gaslini Institute, Genova, Italy

Address reprint requests to Annalisa Pezzolo, PhD, Laboratorio di Oncologia, Istituto Giannina Gaslini 5, 16147 Genova-Quarto, Italy; e-mail: annalisapezzolo{at}ospedale-gaslini.ge.it

Purpose: Malignant cells are genetically unstable and prone to develop chemotherapy resistance, whereas tumor vasculature is usually of host origin and genetically stable. Tumor endothelial microvessels attract interest as therapeutic targets, but their genetic instability would curtail such approach. Here, we have investigated the tumor origin of endothelial microvessels in human neuroblastoma (NB).

Materials and Methods: Paraffin-embedded tissue sections from 10 MYCN-amplified tumors (six stage 4, three stage 3, and one stage 1) were studied. Endothelial cells (ECs) were detected by immunofluorescent staining for CD31 or CD105, and MYCN amplification was detected using fluorescence in situ hybridization (FISH). In xenografts of the HTLA-230 human NB cell line, human ECs were detected by CD31 staining, mouse ECs were detected by CD34 staining, and MYCN amplification and murine DNA were detected using FISH.

Results: MYCN-amplified ECs formed approximately 70% of tumor endothelial microvessels in two stage 4 tumors and 20% in one stage 3 tumor. Similar results were obtained after EC labeling with CD31 or CD105. Staining for alpha-smooth muscle actin in combination with MYCN FISH demonstrated that tumor-derived ECs were coated with pericytes. These vessels were functional because they contained RBCs. Approximately 70% of endothelial vessels from HTLA-230 xenografts stained for human CD31, but not murine CD34, and displayed MYCN amplification, thus proving their tumor origin.

Conclusion: NB-associated endothelial microvessels can originate from tumor cells, and this finding challenges the tenet that tumor vasculature is genetically stable. The possibility that NB-derived ECs are chemotherapy resistant warrants further investigation.

Supported by grants from the Italian Ministry of Health and Compagnia di San Paolo, Torino, Italy.

Presented in part at the Advances in Neuroblastoma Research Meeting, May 17-20, 2006, Los Angeles, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.