Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
Cell Commun Signal. 2018 Apr 6;16(1):13. doi: 10.1186/s12964-018-0225-2.
Osteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence. It is known that malignant phenotypes of OS, such as proliferation, invasion, and metastasis, are significantly influenced not only by characteristics of the tumor itself, but also by the surrounding microenvironment. In other words, OS is considered to utilize cells in the vicinity of the tumor by changing the characteristics of these cells. Direct intercellular contact is believed to be important for this phenomenon. In the present study, we hypothesized that an interaction mediated by a humoral factor, requiring no cellular contact, might play a significant role in the progression of OS.
We developed a new co-culture model, using OS cells and mesenchymal stem cells (MSCs) without cellular contact, and found that both cell types expressed IL-8 at a high level, and FAK in OS cells was phosphorylated leading to an increase in the metastatic potential of the tumor in the co-culture condition.
It was revealed that OS cells formed a loop of signal cross-talk in which they released IL-8 as a paracrine factor, stimulating MSCs to express IL-8, and received IL-8 released by MSCs to accelerate IL-8 expression in OS cells. Administration of anti-IL-8 antibody resulted in the inhibition of FAK expression, its downstream signaling, and the invasive potential of the OS cells, resulting in decrease in metastatic lesions.
The present study might lead not only to the clarification of a new molecular mechanism of invasion and metastasis of OS, but also to the development of a new therapeutic strategy of blocking IL-8 in OS.
骨肉瘤（OS）是最常见的原发性恶性骨肿瘤，发病率最高。已知 OS 的恶性表型，如增殖、侵袭和转移，不仅受肿瘤本身特征的影响，还受周围微环境的影响。换句话说，OS 被认为通过改变这些细胞的特征来利用肿瘤附近的细胞。人们认为细胞间的直接接触对于这种现象很重要。在本研究中，我们假设一种不需要细胞接触的体液因子介导的相互作用可能在 OS 的进展中起重要作用。
我们开发了一种新的共培养模型，使用没有细胞接触的骨肉瘤细胞和间充质干细胞（MSCs），发现两种细胞类型都高水平表达 IL-8，并且骨肉瘤细胞中的 FAK 发生磷酸化，导致肿瘤在共培养条件下的转移潜能增加。
揭示了骨肉瘤细胞形成信号交叉对话的循环，其中它们释放 IL-8 作为旁分泌因子，刺激 MSCs 表达 IL-8，并接收 MSCs 释放的 IL-8 来加速骨肉瘤细胞中 IL-8 的表达。施用抗 IL-8 抗体导致 FAK 表达及其下游信号转导和 OS 细胞的侵袭潜能的抑制，导致转移病变减少。
本研究不仅可能阐明 OS 侵袭和转移的新分子机制，而且可能开发出阻断 OS 中 IL-8 的新治疗策略。
