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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3286-3294.
Prepublished online as a Blood First Edition Paper on December 23, 2004; DOI 10.1182/blood-2004-06-2101.


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NEOPLASIA

Circulating endothelial progenitor cells in multiple myeloma: implications and significance

Hong Zhang, Varsha Vakil, Marc Braunstein, Eric L. P. Smith, Justin Maroney, Laurie Chen, Kezhi Dai, James R. Berenson, M. Mahmood Hussain, Uwe Klueppelberg, Allen J. Norin, Hasan O. Akman, Tayfun Özçelik, and Olcay A. Batuman

From the Division of Hematology/Oncology, the Department of Medicine; the Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY; the Institute for Myeloma & Bone Cancer Research, University of California at Los Angeles (UCLA) School of Medicine, Los Angeles, CA; the Ayhan Sahenk Foundation and Bilkent University, Department of Molecular Biology and Genetics, Bilkent, Ankara, Turkey; the Transplant Immunology & Immunogenetics Laboratory, State University of New York Downstate Medical Center, Brooklyn, NY.

Angiogenesis governs the progression of multiple myeloma (MM). Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease activity and therapeutic response in 31 consecutive patients with MM. CECs, identified as CD34+/CD146+/CD105+/CD11b- cells, were 6-fold higher in patients compared to controls and correlated positively with serum M protein and {beta}2-microglobulin. Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on matrigel; these processes were inhibited after effective thalidomide treatment. Co-expression of vascular endothelial growth factor receptor-2 (KDR) and CD133 characterized EPCs in MM, and KDR mRNA elevations correlated with M protein levels. In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-{beta} and thrombin. Thus, elevated levels of CECs and EPCs covary with disease activity and response to thalidomide, underscoring the angiogenic aspect of MM and suggesting that angioblastlike EPCs are a pathogenic biomarker and a rational treatment target in MM. The results also highlight the anti-angiogenic properties of thalidomide and CC-5013 and further elucidate possible mechanisms of their effectiveness against MM. (Blood. 2005;105:3286-3294)


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