Alterations of Circulating Bone Marrow–Derived VEGFR-2+ Progenitor Cells in Isolated Limb Perfusion With or Without rhTNF-α

• Published in: Annals of surgical oncology Vol. 20; no. 11; pp. 3694 - 3701
• Main Authors: Nowak, Kai, Jachol, Nicole, Rafat, Neysan, Joas, Elena, Beck, Grietje Ch, Hohenberger, Peter
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.10.2013
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bone Marrow - metabolism; Bone Marrow - pathology; Case-Control Studies; Cells, Cultured; Chemotherapy, Cancer, Regional Perfusion; Cisplatin - administration & dosage; Combined Modality Therapy; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Enzyme-Linked Immunosorbent Assay; Extremities; Female; Flow Cytometry; Follow-Up Studies; Healthy Volunteers; Humans; Male; Medicine; Medicine & Public Health; Melanoma - metabolism; Melanoma - pathology; Melanoma - therapy; Melphalan - administration & dosage; Middle Aged; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Neoplasm Staging; Oncology; Prognosis; Recombinant Proteins - therapeutic use; Sarcoma - metabolism; Sarcoma - pathology; Sarcoma - therapy; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; Surgery; Surgical Oncology; Translational Research and Biomarkers; Tumor Necrosis Factor-alpha - administration & dosage; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Young Adult; Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor Level; Melanoma Patient; Isolate Limb Perfusion; Endothelial Progenitor Cell
• ISSN: 1068-9265; 1534-4681; 1534-4681
• DOI: 10.1245/s10434-012-2637-3

Background Circulating endothelial progenitor cells (cEPCs) as recruited to the angiogenic vascular system of malignant tumors have been proposed as a biomarker in malignancies. The effect of antitumor chemotherapy on cEPCs is not fully understood. We examined the level of cEPCs, vascular endothelial growth factor (VEGF), and angiopoietin-2 in the blood of sarcoma and melanoma patients before and after isolated limb perfusion (ILP) with or without recombinant human tumor necrosis factor-α (rhTNF-α). Methods Twenty-two patients, 11 each with soft tissue sarcoma or recurrent melanoma of the limb, were recruited. ILP was performed with rhTNF-α/melphalan (TNF) or melphalan only (no TNF). Fifteen healthy volunteers served as control subjects. Blood was sampled before and up to 6 weeks after ILP. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, and annexin V-negative cells were characterized as cEPCs by triple staining for CD133 + , CD34, and VEGFR-2 + . Results Before treatment, cEPC numbers were significantly increased in sarcoma (0.179 ± 0.190 %) and melanoma patients (0.110 ± 0.073 %) versus healthy controls (0.025 ± 0.018 %; P  < 0.01), but did not differ significantly between sarcoma and melanoma patients. cEPC decreased significantly after ILP in patients with no TNF compared to pretreatment values ( P  < 0.05) and were significantly lower at 4 h, 48 h, and 1 week compared to ILP with TNF ( P  < 0.05). Values 6 weeks after ILP were significantly lower than before ILP in both investigated groups ( P  < 0.01). Conclusions ILP with TNF results in activation of bone marrow–derived EPCs compared to ILP without TNF. Alteration of cEPCs and angiopoietin-2 by rhTNF-α might account for the cytotoxicity and hemorrhagic effects on tumor vessels during limb perfusion procedures.