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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 4040 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.1175
On the Origin and Nature of Elevated Levels of Circulating Endothelial Cells After Treatment With a Vascular Disrupting AgentDepartment of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, University of Toronto, Canada
Department of Hematology-Oncology, European Institute of Oncology, Milan, Italy
Department of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, University of Toronto, Canada To the Editor: We wish to comment on an article by Beerepoot et al1 in the April 1, 2006, issue of the Journal of Clinical Oncology, who report results of a phase I clinical trial testing weekly administration of the vascular disrupting agent (VDA), ZD6126, in patients with solid tumors. In the study, pharmacokinetics, dose-limiting toxicities and biologic effects of escalating doses of ZD6126 administered by weekly infusion were evaluated. Measurements of circulating endothelial cells (CECs) were also carried out by using immunomagnetic beads coupled with a CD146 specific antibody (P1H12), an endothelial cell marker.2 A rapid increase in the level of CECs, detected within hours after the first and second ZD6126 infusions, was reported. The authors suggest that such CECs might be used as a pharmacodynamic surrogate biomarker for damage to the tumor vasculature, an effect which would be expected after VDA treatment given their ability to cause rapid shutdown of the tumor vasculature and apoptosis of activated endothelial cells (for review see Tozer3). CECs can be detected and quantitated using various methods, the most common of which is four color flow cytometry, generally employing several different antibodies to various cell surface markers that are highly specific to endothelial, hematopoietic, and progenitor cells. For example, we have previously described the expression of CD31 and CD146 (both endothelial cell markers), along with absence of both CD133 (a progenitor cell marker) and CD45 (a pan-hematopoietic cell marker) as a phenotype for mature human CECs.4 However, although CD146 is an endothelial cell marker, there are also reports documenting its expression by mononuclear blood cells.5,6 Ninety percent of CD146+ cells were also reported to be CD45+ hematopoietic cells, primarily expressed by a CD3+CD4+ lymphocyte subset5 or activated lymphocytes.6 This information highlights the danger of using this single marker for detecting CECs. While we agree that some of the CD146+ cells detected are indeed likely to be authentic CECs, it is quite plausible that a significant proportion of the cells detected in this study are actually a subset of CECs, namely circulating endothelial progenitor cells, as we previously described,7 which might be rapidly mobilized from the bone marrow by ZD6126 drug activity (for example, as a result, possibly, of disrupting vascular endothelial cadherin function).8 It should also be noted that many of the CECs released into the circulation from damaged vessels are likely dead or apoptotic, especially after treatment with a VDA.3 However, Beereport et al1 did not test the viability of the CD146+ cells. In this regard, we recently reported statistically significant increases in the levels of apoptotic CECs (defined as CECs which are positive to 7-amino-actinomycin) observed in refractory metastatic breast cancer patients who were treated with low-dose metronomic cyclophosphamide and methrotexate.7 Patients responding to treatment showed increased levels of apoptotic but not viable CECs; the likely source of these apoptotic CECs was from the tumor vasculature, based by inference on results using various preclinical models where increases in apoptotic CECs were observed after treatment of tumor bearing but not normal mice treated with metronomic chemotherapy.7 In summary, it is likely that the source of at least some of the CD146+ cells described by Beerepoot et al1, may not be due to damage of the tumor vasculature resulting in shedding of authentic CECs, but rather to mobilization of endothelial progenitor cells and possibly other types of bone marrow derived cells expressing the CD146 marker that potentially contribute to tumor angiogenesis. Thus the use of such a marker (CD146) may not be sufficient to draw firm conclusions about the nature and origin of the cells detected. Authors' Disclosures of Potential Conflicts of Interest The authors ndicated no potential conflicts of interest. REFERENCES
1. Beerepoot LV, Radema SA, Witteveen EO, et al: Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491-1498, 2006 2. St Croix B, Rago C, Velculescu V, et al: Genes expressed in human tumor endothelium. Science 289:1197-1202, 2000 3. Tozer GM, Kanthou C, Baguley BC: Disrupting tumour blood vessels. Nat Rev Cancer 5:423-435, 2005[CrossRef][Medline] 4. Mancuso P, Burlini A, Pruneri G, et al: Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97:3658-3661, 2001 5. Duda DG, Cohen KS, di Tomaso, E, et al: Differential CD146 expression on circulating versus tissue endothelial cells in rectal cancer patients: Implications for circulating endothelial and progenitor cells as biomarkers for antiangiogenic therapy. J Clin Oncol 24:1449-1453, 2006 6. Elshal MF, Khan SS, Takahashi Y, et al: CD146 (Mel-CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood. Blood 106:2923-2924, 2005 7. Mancuso P, Colleoni M, Calleri A, et al: Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108:452-453, 2006 8. Vincent L, Kermani P, Young LM, et al: Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 115:2992-3006, 2005[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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