Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells.
Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells.
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DOI：
10.1158/0008-5472.can-08-0613
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
DeClerck YA
中科院分区：
文献类型：
--
作者：
Ara T;Song L;Shimada H;Keshelava N;Russell HV;Metelitsa LS;Groshen SG;Seeger RC;DeClerck YA
神经母细胞瘤是儿童第二常见的实体瘤，经常转移到骨髓和骨。存在于骨髓中的神经母细胞瘤细胞刺激骨髓基质细胞（BMSC）表达白细胞介素-6（IL-6）以激活破骨细胞。在这里，我们研究了基质来源的IL-6是否也对神经母细胞瘤细胞有旁分泌作用。对11个神经母细胞瘤细胞系中IL-6及其受体IL-6 R表达的分析表明，7个细胞系中表达IL-6，9个细胞系中表达IL-6 R。用rhIL-6处理IL-6 R阳性细胞导致STAT-3和Erk 1/2活化。在BMSC或rhIL-6存在下培养IL-6 R阳性的神经母细胞瘤细胞可增加增殖并保护肿瘤细胞免受依托泊苷诱导的凋亡，而对IL-6 R阴性的肿瘤细胞没有影响。在体内，神经母细胞瘤肿瘤生长更快的IL-6的旁分泌源的存在下。IL-6诱导神经母细胞瘤细胞表达环氧合酶-2，同时释放E2，增加BMSC表达IL-6。支持基质来源的IL-6在神经母细胞瘤骨转移患者中的作用，我们观察到16例神经母细胞瘤骨转移患者的血清和骨髓中IL-6水平升高，以及来自这些患者的BMSC。总之，这些数据表明，基质来源的IL-6有助于形成有利于转移性神经母细胞瘤进展的骨髓微环境。
Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells. An analysis of the expression of IL-6 and its receptor IL-6R in 11 neuroblastoma cell lines indicated the expression of IL-6 in 7 cell lines and of IL-6R in 9 cell lines. Treatment of IL-6R positive cells with rhIL-6 resulted in STAT-3 and Erk 1/2 activation. Culturing IL-6R positive neuroblastoma cells in the presence of BMSC or rhIL-6 increased proliferation and protected tumor cells from etoposide-induced apoptosis, whereas it had no effect on IL-6R negative tumor cells. In vivo, neuroblastoma tumors grew faster in the presence of a paracrine source of IL-6. IL-6 induced the expression of cyclooxygenase-2 in neuroblastoma cells with concomitant release of prostaglandin-E2, that increased the expression of IL-6 by BMSC. Supporting a role for stromal-derived IL-6 in patients with neuroblastoma bone metastasis, we observed elevated levels of IL-6 in the serum and bone marrow of 16 patients with neuroblastoma bone metastasis, and in BMSC derived from these patients. Altogether the data indicate that stromal-derived IL-6 contributes to the formation of a bone marrow microenvironment favorable to the progression of metastatic neuroblastoma.