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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

Dan G. Duda, Kenneth S. Cohen, Emmanuelle di Tomaso, Patrick Au, Rachael J. Klein, David T. Scadden, Christopher G. Willett, Rakesh K. Jain

From the Steele Laboratory for Tumor Biology, Department of Radiation Oncology and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Department of Radiation Oncology, Duke University Medical Center, Durham, NC

Address reprint requests to Dan G. Duda, DMD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, Cox-734, 100 Blossom St, Boston, MA 02114; e-mail: duda{at}steele.mgh.harvard.edu

PURPOSE: Circulating endothelial cells (CECs) and progenitor cells are currently evaluated as potential biomarkers of antiangiogenic therapy. CD146 is considered a panendothelial-specific marker, but its utility as a CEC marker in cancer patients remains unclear.

PATIENTS AND METHODS: We analyzed the expression of CD146 on mononuclear blood cells, primary tissue endothelial cells, and malignant and normal tissues by flow cytometric and immunohistochemical analyses. Furthermore, we measured the circulation kinetics of CD146⁺ cells before, and then 3 and 12 days after vascular endothelial growth factor (VEGF) antibody blockade by bevacizumab infusion in rectal cancer patients enrolled in a phase I trial.

RESULTS: In the peripheral blood of these cancer patients, over 90% of the CD146⁺ cells were CD45⁺ hematopoietic cells. CD146 expression was primarily detected on a subset of CD3⁺CD4⁺ lymphocytes, and was undetectable on CD34⁺CD133⁺CD45^dim progenitor cells or CD31^brightCD45^– viable CECs. In contradistinction, CD146 was detectable in tissues on both cellular components of tumor vessel wall: CD31^brightCD45^– endothelial cells and -SMA⁺ pericytes. Unlike viable CECs and progenitor cells, CD146⁺ cell concentration in the peripheral blood of cancer patients did not decrease during VEGF blockade.

CONCLUSION: CD146 is fairly homogeneously expressed on vascular endothelium but not on viable CECs or progenitor cells. The vast majority of CD146⁺ blood cells are lymphocytes, and VEGF blockade by bevacizumab did not significantly change their number in rectal cancer patients. These results underscore the need for further characterization and identification of new markers for CEC subpopulations for their development as biomarkers of antiangiogenic therapy.

Supported by two National Cancer Institute grants; Grant No. PO1 CA80124 to R.K.J. and Grant No. R21 CA099237 to C.G.W. D.G.D.'s research is supported by an American Association for Cancer Research–Genentech BioOncology Award. D.G.D. is a Cancer Research Institute fellow; P.A. is a fellow of the American Heart Association.

Presented at the 3rd Meeting of the International Society for Stem Cell Research, San Francisco, CA, June 23-25, 2005, and at the American Association for Cancer Research Special Conference on Angiogenesis and Drug Delivery to Tumors: Bench to Bedside and Back, Waltham, MA, November 9-13, 2005.

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

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