Interleukin-6/soluble interleukin-6 receptor signaling attenuates proliferation and invasion, and induces morphological changes of a newly established pleomorphic malignant fibrous histiocytoma cell line
Interleukin-6/soluble interleukin-6 receptor signaling attenuates proliferation and invasion, and induces morphological changes of a newly established pleomorphic malignant fibrous histiocytoma cell line
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DOI：
10.1016/s0002-9440(10)63312-3
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发表时间：
2004-08-01
影响因子：
6
通讯作者：
Itoh, K
中科院分区：
文献类型：
--
作者：
Nakanishi, H;Yoshioka, K;Itoh, K
多形性恶性纤维组织细胞瘤。(MFH)偶尔与炎性副肿瘤综合征（PNS）有关。近年来，我们发现白细胞介素6（interleukin-6，IL-6）可能是MFH的一种肿瘤相关因子，参与了MFH的发病机制和临床表现。在局部微环境中，肿瘤诱导的炎症反应可能在促进肿瘤进展中发挥作用。为了阐明IL-6在MFH中的生物学相关性，我们建立了一种人MFH细胞系，命名为MIPS-2，来源于PNS患者的切除标本。在该患者中，血清IL-6水平与病程平行：血清IL-6浓度升高在根治性手术后立即恢复正常，肿瘤复发时再升高。MIPS-2表现为多形性外观，严重的核异常，核仁突出，并在裸鼠体内成瘤。MIPS-2表达IL-6、IL-6受体（IL-6 R）和糖蛋白130（gp 130），但缺乏可溶性形式的IL-6 R（sIL-6 R），如通过流式细胞术和逆转录聚合酶链反应分析所确定的。用IL-6和外源性sIL-6 R联合刺激MIPS-2可诱导信号转导和转录激活因子3（STAT 3）和丝裂原活化蛋白激酶（MAPK）磷酸化，降低细胞增殖，减弱侵袭力，并诱导形态学改变。这些结果提示IL-6/sIL-6 R信号通路通过STAT 3和MAPK通路以自分泌和/或旁分泌的方式在MFH的增殖、侵袭和形态学中起着关键作用，并提出了使用抗生长因子和促炎性丝氨酸靶向策略来对抗破坏性MFH的治疗潜力。
Pleomorphic malignant fibrous histiocytoma. (MFH) is occasionally associated with inflammatory paraneoplastic syndrome (PNS). Recently, we reported that interleukin (IL)-6, one of the candidate cytokines, which induces such systemic inflammatory reaction, may be a tumor-associated factor involved in the pathogenesis and its clinical manifestations of MFH. In the local microenvironment, tumor-induced inflammatory reaction may play a role favoring tumor progression. To clarify the biological relevance of IL-6 in MFH, we established a human MFH cell line, named MIPS-2, derived from a resected specimen of a patient presenting with PNS. In this patient, the serum IL-6 level ran parallel to the disease course: elevated serum IL-6 concentration normalized immediately after radical surgery, and re-elevation occurred on tumor recurrence. MIPS-2 presented pleomorphic appearance, severe nuclear abnormalities with prominent nucleoli, and tumorigenesis in nude mice. MIPS-2 expressed IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) but lacked the soluble form of IL-6R (sIL-6R), as determined by flow cytometry and reverse transcriptase-polymerase chain reaction analyses. Stimulation of MIPS-2 with IL-6 combined with exogenous sIL-6R induced phosphorylation of both signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK), decreased cell proliferation, attenuated invasion, and induced morphological changes. Collectively, these data suggested that the IL-6/sIL-6R signaling pathway plays a pivotal role for proliferation, invasion, and morphology of MFH via STAT3 and MAPK pathway as autocrine and/or paracrine manner, and proposed the therapeutic potential for the use of both anti-growth factor and proinflammatory cytokine-targeting strategies to combat devastating MFH.