Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis
Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis
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DOI：
10.1182/blood-2002-10-3000
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发表时间：
2003-04-15
期刊：
影响因子：
20.3
通讯作者：
Vanderkerken, K
中科院分区：
文献类型：
--
作者：
Asosingh, K;De Raeve, H;Vanderkerken, K
在临床表现上，多发性骨髓瘤（MM）已经是一种公认的疾病。然而，早期阶段所涉及的过程是未知的。在此，5 T2 MM鼠模型用于分析疾病进展期间MM细胞的分化、增殖、侵袭和凋亡。给未处理小鼠注射5 T2 MM细胞，从实验开始，每周处死3只小鼠，直到结束阶段。从骨髓中分离骨髓瘤细胞，并通过流式细胞术连续门控5 T2 MM独特型（+）细胞进行选择。这些分选的5 T2 MM同种型（+）细胞的显微镜分析证实了其为真正的骨髓瘤细胞。根据血清副蛋白浓度和骨髓肿瘤负荷，区分3个疾病阶段：静止期、中间期和终末期，分别为缓慢、中度和加速肿瘤进展。在静止期，大多数骨髓瘤细胞为CD 45（+）CD 138（-）IL-6 Ra（+），对应于未成熟、侵袭性和抗肿瘤表型。在终末期，大多数骨髓瘤细胞已分化为CD 45（-）CD 138（+）IL-6 R α（-）细胞，对应于成熟、侵袭性较低和对骨髓瘤敏感的表型。在中间阶段，观察到从静止向结束阶段的逐渐过渡。与这些数据一致，对分选的5 T2 MM细胞的分析表明，在疾病进展期间，侵袭能力显著降低，（地塞米松诱导的）凋亡敏感性和增殖显著增加。这些数据表明，骨髓瘤疾病的进展是一个多阶段的动态过程中的分化，增殖，侵袭和凋亡。(C)2003年，美国血液学会。
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 idlotype(+) 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-6Ra(+), 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-6Ralpha(-) 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. (C) 2003 by The American Society of Hematology.