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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-10-3000.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3136-3141
NEOPLASIA
Multiple myeloma tumor progression in the 5T2MM murine
model is a multistage and dynamic process of differentiation,
proliferation, invasion, and apoptosis
Kewal Asosingh,
Hendrik De Raeve,
Ivan Van
Riet,
Benjamin Van Camp, and
Karin Vanderkerken
From the Department of Hematology and Immunology, Vrije
Universiteit Brussel, Brussels, Belgium; and the
Department of Pathology, Universitair Instituut Antwerpen, Antwerp,
Belgium.
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 3 mice were killed each week until
the end stage. Myeloma cells were isolated from the bone marrow and
selected by sequential gating of 5T2MM idiotype+ cells by
flow cytometry. Microscopic analysis of these sorted 5T2MM
idiotype+ cells confirmed their identity as true myeloma
cells. Based on serum paraprotein concentration and bone marrow tumor
load, 3 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,
the majority of the myeloma cells were
CD45+CD138 IL-6R +,
corresponding to an immature, invasive, and apoptosis-resistant phenotype. In the end stage the majority of the myeloma cells had
differentiated into
CD45CD138+IL-6R cells,
corresponding to a mature, less invasive, and apoptosis-sensitive phenotype. In the intermediate stage a gradual transition from the
quiescent toward 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
multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis.
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