High Levels of Circulating VEGFR2+ Bone Marrow–Derived Progenitor Cells Correlate with Metastatic Disease in Patients with Pediatric Solid Malignancies

• Published in: Clinical cancer research Vol. 15; no. 14; pp. 4561 - 4571
• Main Authors: Taylor, Melissa, Rössler, Jochen, Geoerger, Birgit, Laplanche, Agnès, Hartmann, Olivier, Vassal, Gilles, Farace, Françoise
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2009
• Subjects: Antigens, CD34 - blood; Antineoplastic agents; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; CD146 Antigen - blood; Child; Child, Preschool; Endothelial Cells - metabolism; Endothelial Cells - pathology; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Infant; Leukocyte Common Antigens - blood; Male; Medical sciences; Neoplasm Metastasis; Neoplasms - blood; Neoplasms - blood supply; Neoplasms - pathology; Neovascularization, Pathologic - blood; Neovascularization, Pathologic - pathology; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - blood; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor Receptor-2 - blood; Young Adult; Human; Pediatrics; Disease; Stem cell; Patient; Infant; Malignancy; Metastasis; Malignant tumor; Bone marrow; Advanced stage; Child; Cancer; Progenitor cell
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2363

Purpose: Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow–derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. Patients and Methods: Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45−CD34+VEGFR2(KDR)+7AAD− and CD45dimCD34+VEGFR2+7AAD− events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45−7AAD− viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. Results: The CD45−CD34+VEGFR2(KDR)+7AAD− subset represented <0.003% of circulating BMD progenitor cells (≤0.05 cells/mL). However, the median level (range) of the CD45dimCD34+VEGFR2+7AAD− subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. Conclusion: High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.