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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3131-3137.
Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-08-2946.
Submitted August 27, 2003
Accepted November 21, 2003
Angiogenic switch during 5T2MM murine myeloma tumorigenesis; role of CD45 heterogeneity
Kewal Asosingh*, Hendrik De Raeve, Eline Menu, Ivan Van Riet, Eric Van Marck, Benjamin Van Camp, and Karin Vanderkerken
Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
Department of Pathology, Universitair Instituut Antwerpen, Antwerp, Belgium
* Corresponding author; email: Kewal.Asosingh{at}vub.ac.be.
The active role of angiogenesis during disease progression is well recognized in solid tumors. In hematological malignancies, such as multiple myeloma (MM) it is not known whether tumor neovascularization is an epiphenomenon or whether it is actively involved in disease progression. At clinical presentation myeloma disease and the associated angiogenesis are both well established. Here the 5T2MM murine model was used to analyze angiogenesis during pre-clinical myeloma stages. Bone marrow (BM) of 5T2MM inoculated mice were analyzed at weekly intervals until the end stage of the disease. Histological analysis and assessment of microvessel density (MVD) by CD31 staining demonstrated a pre-angiogenic stage of small tumor aggregates followed by an angiogenic switch and subsequently an angiogenic stage of progressive tumor growth and large, confluent tumor nodules. Flow cytometric analysis that indicated an increase in percentage CD45- MM cells preceded the angiogenic switch. RT-PCR of sorted CD45+ and CD45- MM cells indicated higher VEGF120 and VEGF164 transcripts in CD45- MM cells. VEGF ELISA revealed high secretion by CD45- MM cells, but no protein secretion by CD45+ MM cells, indicating angiogenic heterogeneity among the MM cells. These data suggest that like in solid tumors angiogenic switch and angiogenic heterogeneity exist in MM.
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