Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis.
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 alpha(+), corresponding to an immature, invasive, and apoptosis-resistant phenotype. In the end stage the majority of the myeloma cells had differentiated into CD45(-)CD138(+)IL-6R alpha(-) 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.
Asosingh
Kewal
K
Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium. asosingh@vub.ac.be
De Raeve
Hendrik
H
Van Riet
Ivan
I
Van Camp
Benjamin
B
Vanderkerken
Karin
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002455:Cell Division; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D018450:Disease Progression; D005434:Flow Cytometry; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000097:blood / Q000473:pathology*; D009194:Myeloma Proteins / Q000032:analysis; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000032:analysis; D053668:Syndecan-1; D053667:Syndecans; D014407:Tumor Cells, Cultured / Q000187:drug effects
D008562:Membrane Glycoproteins; D009194:Myeloma Proteins; D011509:Proteoglycans; D019947:Receptors, Interleukin-6; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D003907:Dexamethasone; D017493:Leukocyte Common Antigens