文章：

癌症中的MSP-RON信号：发病机制和治疗潜力

MSP–RON signalling in cancer: pathogenesis and therapeutic potential

原文发布日期：2013-01-10

DOI: 10.1038/nrc3545

类型: Review Article

开放获取: 否

要点：

1. Macrophage-stimulating protein (MSP; also known as MST1 and hepatocye growth factor-like (HGFL)), is a serum-derived growth factor that activates the RON receptor tyrosine kinase. RON signalling is essential for the survival of embryos during the peri-implantation period. Cancer cells use MSP–RON signalling for survival, migration, angiogenesis and chemoresistance, which has pathogenic implications.
2. Crystal structure analyses have shown that a central cleft harbouring three amino acid residues in the putative catalytic site of the MSP β-chain interacts with an interface created by two RON semaphorin (SEMA) domains. This supports a model in which one MSP molecule binds two RON molecules to cause receptor dimerization and activation.
3. Aberrant RON activation, which is induced by overexpression of protein and the generation of oncogenic isoforms and is indicated by the persistent activation of multi-intracellular signalling cascades, occurs in various types of cancers. RON signalling is also necessary for cancer cell growth and survival. These features render RON as a drug target for cancer therapy.
4. MSP–RON signalling activates two classical signalling pathways, RAS–ERK and PI3K–AKT, both of which interact with various other pathways to create a complex signalling network. RON also crosstalks with other receptor tyrosine kinases and viral oncoproteins. Such intricate interactions highlight the importance of RON signalling in cancer pathogenesis.
5. Overexpression of RON in primary tumours such as colon and breast cancer is predictive of patient survival and correlates with clinical and pathological parameters.
6. Studies from mouse xenograft models have revealed that inhibition of RON by tyrosine kinase inhibitors and monoclonal antibodies blocks tumour growth. However, combinations with chemoagents achieve maximum therapeutic benefit. The tyrosine kinase inhibitor BMS-777607 and the RON-specific antibody narnatumab are currently in Phase I clinical trials.

要点翻译：

1. 巨噬细胞刺激蛋白（MSP，亦称MST1及肝细胞生长因子样蛋白）是一种血清源性生长因子，可激活RON受体酪氨酸激酶。RON信号传导在胚胎植入前后的存活过程中起关键作用。癌细胞利用MSP-RON信号通路实现存活、迁移、血管生成及化疗耐药，这一过程具有致病意义。
2. 晶体结构分析表明，MSPβ链推定催化中心存在一个容纳三个氨基酸残基的裂隙结构，该结构与两个RON信号素结构域形成的界面相互作用。这支持了单个MSP分子结合两个RON分子从而诱导受体二聚化与激活的模型。
3. 异常RON激活可见于多种癌症，其诱因包括蛋白过表达及致癌异构体的产生，并通过多重细胞内信号级联的持续激活来体现。RON信号传导对癌细胞的生长与存活至关重要，这些特性使RON成为癌症治疗的药物靶点。
4. MSP-RON信号通路可激活RAS-ERK和PI3K-AKT两条经典信号途径，二者通过与其他多种通路相互作用形成复杂的信号网络。RON还能与其他受体酪氨酸激酶及病毒癌蛋白发生交叉对话。这种错综复杂的相互作用凸显了RON信号在癌症发病机制中的重要性。
5. 在结直肠癌和乳腺癌等原发肿瘤中，RON的过表达可作为患者生存期的预测指标，并与临床病理参数相关。
6. 小鼠移植瘤模型研究表明，酪氨酸激酶抑制剂和单克隆抗体对RON的抑制能阻断肿瘤生长。但与化疗药物联用可获得最大疗效。酪氨酸激酶抑制剂BMS-777607和RON特异性抗体narnatumab目前正处于I期临床试验阶段。

英文摘要：

Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP–RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP–RON signalling in cancer and its potential as a therapeutic target.

摘要翻译： 

自20世纪90年代初发现巨噬细胞刺激蛋白（MSP，又称MST1或肝细胞生长因子样蛋白HGFL）作为受体酪氨酸激酶RON（又称MST1R）的配体以来，该信号轴在癌症发病机制中的作用已在多种模型系统中被广泛研究。体外和体内证据均表明，MSP-RON信号对不同癌症的侵袭性生长至关重要。目前，小分子抑制剂和阻断RON信号的单抗正在研究中。人肿瘤异种移植模型已观察到显著疗效，为临床验证奠定了基础。本综述将讨论近期进展，阐述MSP-RON信号在癌症中的重要性及其作为治疗靶点的潜力。

原文链接：

MSP–RON signalling in cancer: pathogenesis and therapeutic potential