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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-10-3000.
Submitted October 3, 2002
Accepted November 22, 2002
Multiple myeloma tumor progression in the 5T2 murine model is a multi-stage and dynamic process of differentiation, proliferation, invasion and apoptosis
Kewal Asosingh*, Hendrik De Raeve, Ivan Van Riet, Benjamin Van Camp, and Karin Vanderkerken
Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
Pathology, Universitair Insituut Antwerpen, Antwerp, Belgium
* Corresponding author; email: Kewal.Asosingh{at}vub.ac.be.
At clinical presentation, multiple myeloma (MM) is already a well established disease. The processes involved in earlier stages are, however, unknown. Here the 5T2MM murine model was used to analyze differentiation, proliferation, invasion and apoptosis of MM cells during disease progression. Naive mice were injected with 5T2MM cells and from the onset of the experiment three mice were sacrificed in time intervals of one week until the end stage. Myeloma cells were isolated from the bone marrow and selected by sequential gating of 5T2MM idiotype positive cells by flow cytometry. Microscopic analysis of these sorted 5T2MM idiotype positive cells confirmed their identity as true myeloma cells. Based on serum paraprotein concentration and BM tumor load three disease stages were distinguished: a quiescent stage, an intermediate stage and an end stage of slow, moderate and accelerated tumor progression, respectively. In the quiescent stage, majority of the myeloma cells were CD45+CD138-IL-6R +, corresponding with an immature, invasive and apoptosis resistant phenotype. In the end stage the majority of the myeloma cells had differentiated into CD45-CD138+IL6R-, cells corresponding with a mature, less invasive and apoptosis sensitive phenotype. In the intermediate stage a gradual transition from the quiescent towards the end stage was observed. In line with these data, analysis of sorted 5T2MM cells demonstrated a significant decrease in invasive capacity and a significant increase in (Dexamethasone-induced)apoptosis sensitivity and in proliferation during the disease progression. These data suggest that myeloma disease progression is a multi-stage and dynamic process of differentiation, proliferation, invasion and apoptosis.
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