Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma
Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma
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DOI：
10.1080/2162402x.2015.1008850
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发表时间：
2015-06-01
期刊：
影响因子：
7.2
通讯作者：
Bellone, Matteo
中科院分区：
文献类型：
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作者：
Calcinotto, Arianna;Ponzoni, Maurilio;Bellone, Matteo
虽然多发性骨髓瘤（MM）几乎总是以无症状的未确定意义的单克隆γ病（MGUS）和/或阴发性骨髓瘤（SMM）为先兆，但确定进展为症状性疾病的骨髓（BM）微环境的改变是间接的。本研究表明，在携带癌基因驱动的浆细胞增殖性疾病的Vk*MYC小鼠中，疾病的出现与BM微环境的实质性改变有关，包括CD8（+）和CD4(+) T细胞的进行性积累，并伴有显性T辅助型1 （Th1）反应。从无症状到有症状的MM的进展特征是T细胞的进一步BM积累，Th1减少，Th2细胞因子的产生持续增加，这与CD206(+)Tie2（+）巨噬细胞的积累、促血管生成细胞因子和微血管密度（MVD）的增加有关。值得注意的是，与处于静止状态的MGUS和SMM患者相比，MGUS和SMM患者的BM诊断时MVD也增加，随后进展为MM。这些发现提示MM有一个多步骤的致病过程，其中免疫系统可能促进血管生成和疾病进展。他们还建议启动一项大型多中心研究，以调查无症状患者的MVD作为该疾病进展和结局的预后因素。
While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8(+) and CD4(+) T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206(+)Tie2(+) macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease.