This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ruan, J. Articles by Rafii, S. Search for Related Content PubMed PubMed Citation Articles by Ruan, J. Articles by Rafii, S.

Magnitude of Stromal Hemangiogenesis Correlates with Histologic Subtype of Non–Hodgkin's Lymphoma

Authors' Affiliations: ¹ Center for Lymphoma and Myeloma, ² Division of Hematology-Oncology, Department of Medicine, ³ Department of Pathology, ⁴ Division of Biostatistics and Epidemiology, Department of Public Health, ⁵ Department of Genetic Medicine, and ⁶ Howard Hughes Medical Institute, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Shahin Rafii, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, Room A-863, New York, NY 10021. Phone: 212-746-2070; Fax: 212-746-8481; E-mail: srafii{at}med.cornell.edu and Jia Ruan, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, 520 East 70th Street, Starr 341, New York, NY 10021. Phone: 212-746-2932; Fax: 212-746-3844; E-mail: jruan{at}med.cornell.edu.

Purpose: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1⁺ (VEGFR-1⁺) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68⁺ hemangiogenic cells and -smooth muscle actin⁺ (-SMA⁺) stromal cells correlates with neoangiogenesis and progression in human non–Hodgkin's lymphoma subtypes.

Experimental Design: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, -SMA, and CD68 were examined by immunohistochemistry in 42 cases of non–Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia.

Results: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68⁺ cells and VEGFR-1⁺ neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68⁺ cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68⁺ cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in -SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34⁺ microvessel density and lymphoma histologic subtype.

Conclusions: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1⁺CD68⁺VEGF-A⁺ cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas -SMA⁺ stromal vascular network may be differentially targeted in CLL/SLL.

This article has been cited by other articles:

				A. Zucchetto, D. Benedetti, C. Tripodo, R. Bomben, M. Dal Bo, D. Marconi, F. Bossi, D. Lorenzon, M. Degan, F. M. Rossi, et al. CD38/CD31, the CCL3 and CCL4 Chemokines, and CD49d/Vascular Cell Adhesion Molecule-1 Are Interchained by Sequential Events Sustaining Chronic Lymphocytic Leukemia Cell Survival Cancer Res., May 1, 2009; 69(9): 4001 - 4009. [Abstract] [Full Text] [PDF]

				J. Ruan, K. Hajjar, S. Rafii, and J. P. Leonard Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma Ann. Onc., March 1, 2009; 20(3): 413 - 424. [Abstract] [Full Text] [PDF]

				S. Kusmartsev, E. Eruslanov, H. Kubler, T. Tseng, Y. Sakai, Z. Su, S. Kaliberov, A. Heiser, C. Rosser, P. Dahm, et al. Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma J. Immunol., July 1, 2008; 181(1): 346 - 353. [Abstract] [Full Text] [PDF]

				A. Burkle, M. Niedermeier, A. Schmitt-Graff, W. G. Wierda, M. J. Keating, and J. A. Burger Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia Blood, November 1, 2007; 110(9): 3316 - 3325. [Abstract] [Full Text] [PDF]