SHP2与乳腺癌侵袭转移相关性的研究进展

含Src同源区2蛋白质酪氨酸磷酸酶（Src homology 2 domain containing protein tyrosine phosphatases,SHP2）是一种跨膜型蛋白酪氨酸磷酸酶,通过调节细胞内蛋白质的酪氨酸磷酸化水平,在细胞信号转导通路及控制细胞活性中发挥重要的作用。其活化状态与乳腺癌发生发展过程中的Ras/ERK,PI3K/Akt/mTOR等信号通路、激素水平、侵袭转移、肿瘤干细胞的生物学行为等密切相关。SHP2基因的敲除或抑制SHP2蛋白表达,可不同程度阻断与乳腺癌侵袭、转移相关的信号通路,从而抑制肿瘤生长,甚至不可逆地使肿瘤丧失重新获得干细胞特性的能力。因此,SHP2很可能为抗肿瘤药物的研发提供一个新的靶点。本文就SHP2与乳腺癌侵袭转移的相关研究进展进行综述。      

SHP2靶向治疗在抗肿瘤研究中的进展

免疫治疗和靶向治疗是目前抗肿瘤精准治疗的主要方式,但耐药性的出现导致一些肿瘤患者无法从临床治疗中获益。含Src同源2结构域的蛋白酪氨酸磷酸酶2（Src homology 2 domain-containing protein tyrosine phosphatase 2,SHP2）参与细胞内多种级联信号通路。基于底物特异性的SHP2在不同组织类型的背景下,发挥着促癌或者抑癌的重要作用。近几年随着多种新开发的SHP2变构抑制剂的出现,SHP2已成为一些肿瘤的潜在药物靶点。对一些临床前癌症模型的研究表明,SHP2变构抑制剂与其他靶向药和/或免疫检查点阻断剂联合使用是精准治疗耐药癌症的一种很有前景的策略。本文主要综述了近年来SHP2在肿瘤和免疫细胞中的作用机制、在临床前模型中的肿瘤靶向和免疫治疗研究以及SHP2抑制剂在临床试验中的研究进展。     

Sprouty 在肿瘤中的研究进展

Sprouty 蛋白是受体酪氨酸激酶（receptor tyrosine kinase ,RTK ）等信号通路的抑制因子。Sprouty 蛋白家族在多种肿瘤组织中表达降低,导致RTK 等信号通路失去正常的抑制,造成肿瘤细胞异常增殖,从而促进肿瘤的发生及发展,因而Sprouty 成为当前肿瘤靶向治疗的研究热点。本文就Sprouty 与肿瘤发生、发展关系及其在肿瘤中的研究进展进行综述。      

基于酪氨酸磷酸酶SHP2变构抑制剂的肿瘤靶向治疗

[摘要] 蛋白质酪氨酸磷酸化对细胞的生命活动至关重要,其调控异常与多种疾病的发生密切相关。在酪氨酸磷酸酶家族中,SHP2 是目前唯一被证实的原癌蛋白,参与调控多个癌症相关过程。其活化突变会导致白血病、黑色素瘤、乳腺癌及肺癌的发生。2016 年以来,随着高特异性、可口服的SHP2 新型变构抑制剂成功开发,靶向抑制SHP2 在抑制肿瘤生长以及改善肿瘤耐药性方面逐渐显现出了强大的临床应用潜力,提示SHP2 抑制剂有望成为首个靶向酪氨酸磷酸酶的抗肿瘤靶向药物。     

支架蛋白Gab2与肿瘤关系的研究进展

Gab2是Gabs家族蛋白中一种至关重要的信号中介分子,该家族蛋白通过接受多种生长因子、细胞因子及抗原等胞外刺激,参与信号转导的放大及整合。Gab2蛋白被蛋白酪氨酸激酶磷酸化激活后,招募富含SH2结构域的信号效应蛋白如SHP2、 PI3K的p85亚基、Crk和GC-GAP,主要介导SHP2/RAS/ERK和PI3K/AKT两条经典的信号通路,在多种生理学及病理学过程中发挥重要作用。近年研究发现,异常的Gab2及其信号与乳腺癌、白血病及黑色素瘤等其他人类肿瘤密切相关。本文就Gab2蛋白的结构、信号调控及在肿瘤中的研究进展进行综述。     

MyD88在肿瘤免疫耐受及免疫治疗中的研究进展

摘 要：MyD88作为一种通用的信号衔接蛋白,调节大多数Toll样受体（TLR）和白细胞介素1受体（IL-1R）级联的信号传导,参与介导先天免疫,调节炎症微环境和肿瘤微环境。通过TLR/MyD88信号途径,MyD88直接或间接地影响多种下游的免疫因子分泌,诱导肿瘤细胞和/或免疫细胞分泌蛋白或表面分子改变,同时引起肿瘤组织局部免疫细胞种类、数量及功能的改变,导致炎症微环境恶化及肿瘤微环境重塑,最终引起肿瘤免疫耐受和免疫逃逸。MyD88在肿瘤免疫治疗中具有双重作用,一方面通过分泌免疫抑制因子,抑制疗效;另一方面将MyD88信号与嵌合抗原受体（CAR）T细胞、特异性抗原肽等新兴疗法结合,大大提高肿瘤免疫治疗的效率。MyD88的上述作用使其成为多种恶性肿瘤极具前景的诊疗靶点。摘 要：MyD88作为一种通用的信号衔接蛋白,调节大多数Toll样受体（TLR）和白细胞介素1受体（IL-1R）级联的信号传导,参与介导先天免疫,调节炎症微环境和肿瘤微环境。通过TLR/MyD88信号途径,MyD88直接或间接地影响多种下游的免疫因子分泌,诱导肿瘤细胞和/或免疫细胞分泌蛋白或表面分子改变,同时引起肿瘤组织局部免疫细胞种类、数量及功能的改变,导致炎症微环境恶化及肿瘤微环境重塑,最终引起肿瘤免疫耐受和免疫逃逸。MyD88在肿瘤免疫治疗中具有双重作用,一方面通过分泌免疫抑制因子,抑制疗效;另一方面将MyD88信号与嵌合抗原受体（CAR）T细胞、特异性抗原肽等新兴疗法结合,大大提高肿瘤免疫治疗的效率。MyD88的上述作用使其成为多种恶性肿瘤极具前景的诊疗靶点。     

靶向缺氧肿瘤微环境在多发性骨髓瘤治疗中的机制研究进展

多发性骨髓瘤（multiple myeloma,MM）作为一种高度异质性的难治性浆细胞肿瘤,与多数实体瘤类似,暴露于缺氧的肿瘤微环境中。缺氧条件下促进缺氧诱导因子（hypoxia inducible factor-1,HIF-1）活化及其作为转录因子参与的下游信号通路的激活,作用于肿瘤血管形成,骨髓瘤细胞的播散与转移,影响抗肿瘤免疫,促进肿瘤免疫逃逸,以及改变细胞能量代谢,参与诱导治疗耐药。基于上述机制,本文分别从靶向HIFs因子或信号通路的直接抑制,改善代谢、增加氧合,靶向免疫检查点恢复有效肿瘤免疫,抗血管形成等方面对靶向缺氧微环境的治疗在MM中的研究现状进行综述。     

受体酪氨酸激酶抑制剂在恶性胶质瘤中的临床试验进展

恶性胶质瘤的发生发展与受体酪氨酸激酶（RTK）过表达及其信号转导通路的异常激活密切相关,据此开发出的靶向治疗药物如RTK抑制剂、RTK下游信号通路抑制剂和多靶点抑制剂等能在分子水平上对恶性胶质瘤进行靶向性治疗,其中部分已通过临床试验,并取得良好疗效。     

抗成纤维细胞生长因子及其受体信号通路药物在肿瘤治疗中应用的研究进展

成纤维细胞生长因子受体（FGFR）是一种受体酪氨酸激酶（RTK），与其配体成纤维细胞生长因子（FGF）相结合，激活下游的信号转导通路，参与调控细胞的正常生理活动。当FGFR基因发生扩增、突变或者融合等异常改变时，就会导致下游细胞信号通路的异常激活，促进细胞的增殖、迁移、侵袭及上皮-间质转化，进而促进肿瘤的发展。同时，FGFR在多种肿瘤中均呈高表达，因此FGF/FGFR可作为肿瘤治疗的重要靶点。根据药物作用机制，可以将抗FGFR信号通路药物分为两大类，分别为FGFR-酪氨酸激酶抑制剂（TKI）和阻断FGF/FGFR的单克隆抗体。目前，已有多种针对FGF/FGFR的靶向药物进入临床试验阶段，在肿瘤治疗中取得较好的临床效果，有的靶向药物获批用于临床肿瘤的治疗，为肿瘤的精准治疗带来了新的曙光。     

肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。     

Targeting PTPs with small molecule inhibitors in cancer treatment

Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the phosphatase of regenerating liver (PRL) phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.     

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

Receptor tyrosine kinases (RTKs) such as the fibroblast growth factor receptor (FGFR) and the epidermal growth factor receptor are overexpressed in a variety of cancers. In addition to overexpression, the FGFRs are found mutated in some cancers. The Src homology 2 domain-containing phosphotyrosine phosphatase (SHP2) is a critical mediator of RTK signaling, but its role in oncogenic RTK-induced cell transformation and cancer development is largely unknown. In the current report, we demonstrate that constitutively activated FGFR3 (K/E-FR3) transforms NIH-3T3 cells, and that SHP2 is a critical mediator of this transformation. Infection of K/E-FR3-transformed 3T3 cells with a retrovirus carrying a dominant-negative mutant of SHP2 (C/S-SHP2) retarded cell growth, reversed the transformation phenotype and inhibited focus-forming ability. Furthermore, treatment of K/E-FR3-transformed NIH-3T3 cells with PD98059 or LY294002, specific inhibitors of MEK and PI3K, respectively, inhibited focus formation. Biochemical analysis showed that K/E-FR3 activates the Ras-ERK and the PI3K signaling pathways, and that the C/S SHP2 mutant suppressed this effect via competitive displacement of interaction of the endogenous SHP2 with FRS2. However, the C/S SHP2 protein did not show any effect on receptor autophosphorylation, FRS2 tyrosine phosphorylation or interaction of Grb2 with K/E-FR3 or FRS2. Together, the results show that K/E-FR3 is transforming and that the Ras-ERK and the PI3K-Akt signaling pathways, which are positively regulated by SHP2, are important for K/E-FR3-induced transformation.     

Overexpression and activation of epidermal growth factor receptor in hemangioblastomas

Hemangioblastomas frequently develop in patients with von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder. The tumors are characterized by a dense network of blood capillaries, often in association with cysts. Although activation of receptor tyrosine kinase (RTK) signaling, including epidermal growth factor receptor (EGFR) has been implicated in the development of malignant brain tumors such as high-grade gliomas, little is known about the role of RTK signaling in hemangioblastomas. To address this issue, we examined hemangioblastoma tumor specimens using receptor tyrosine kinase (RTK) activation profiling and immunohistochemistry. Six human hemangioblastomas were analyzed with a phospho-RTK antibody array, revealing EGFR phosphorylation in all tumors. EGFR expression was confirmed by immunohistochemistry in all tumors analyzed and downstream effector pathway activation was demonstrated by positive staining for phospho-AKT. Our findings suggest that, in primary hemangioblastomas, RTK upregulation and signaling predominantly involves EGFR, providing an attractive molecular target for therapeutic intervention.     

The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V

Activated forms of the platelet derived growth factor receptor alpha (PDGFRα) have been described in various tumors, including FIP1L1-PDGFRα in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFRα^D842V mutant in gastrointestinal stromal tumors and inflammatory fibroid polyps.To gain a better insight into the signal transduction mechanisms of PDGFRα oncogenes, we mutated twelve potentially phosphorylated tyrosine residues of FIP1L1-PDGFRα and identified three mutations that affected cell proliferation. In particular, mutation of tyrosine 720 in FIP1L1-PDGFRα or PDGFRα^D842V inhibited cell growth and blocked ERK signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of human CD34⁺ hematopoietic progenitors transduced with FIP1L1-PDGFRα. We showed that the non-receptor protein tyrosine phosphatase SHP2 bound directly to tyrosine 720 of FIP1L1-PDGFRα. SHP2 knock-down decreased proliferation of Ba/F3 cells transformed with FIP1L1-PDGFRα and PDGFRα^D842V and affected ERK signaling, but not STAT5 phosphorylation. Remarkably, SHP2 was not essential for cell proliferation and ERK phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation, suggesting a shift in the function of SHP2 downstream of oncogenic receptors.In conclusion, our results indicate that SHP2 is required for cell transformation and ERK activation by mutant PDGF receptors.     

Protein tyrosine phosphatase SHP2 promotes invadopodia formation through suppression of Rho signaling

Invadopodia are actin-enriched membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Src homolog domain-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, has been shown to play an important role in promoting cancer metastasis, but the underlying mechanism is unclear. In this study, we found that depletion of SHP2 by short-hairpin RNA suppressed invadopodia formation in several cancer cell lines, particularly in the SAS head and neck squamous cell line. In contrast, overexpression of SHP2 promoted invadopodia formation in the CAL27 head and neck squamous cell line, which expresses low levels of endogenous SHP2. The depletion of SHP2 in SAS cells significantly decreased their invasive motility. The suppression of invadopodia formation by SHP2 depletion was restored by the Clostridium botulinum C3 exoenzyme (a Rho GTPase inhibitor) or Y27632 (a specific inhibitor for Rho-associated kinase). Together, our results suggest that SHP2 may promote invadopodia formation through inhibition of Rho signaling in cancer cells.     

糖尿病与肿瘤关系的研究进展

2型糖尿病和肿瘤是两类严重威胁人类健康的慢性疾病。大量的流行病学和临床研究表明,2型糖尿病患者肝癌、胰腺癌、子宫内膜癌、胆囊癌、结直肠癌和乳腺癌的风险增加。高血糖可通过多种直接和间接机制促进癌细胞增殖、迁移、侵袭和免疫逃逸。胰岛素抵抗和高胰岛素血症会通过胰岛素/IGF-I信号轴激活多条信号通路促进肿瘤发生。持续的慢性炎性反应可通过DNA损伤和促炎因子促进癌症的发生发展。肠道菌群失调主要与几种消化道肿瘤发生密切相关。本文将对2型糖尿病与恶性肿瘤发生发展的关系及可能的机制研究进展进行综述。     

Receptor-type Protein Tyrosine Phosphatase �� Regulates Met Phosphorylation and Function in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and has a high rate of mortality. Emerging evidence indicates that hepatocyte growth factor receptor (or Met) pathway plays a pivotal role in HNSCC metastasis and resistance to chemotherapy. Met function is dependent on tyrosine phosphorylation that is under direct control by receptor-type protein tyrosine phosphatase β (RPTP-β). We report here that RPTP-β expression is significantly downregulated in HNSCC cells derived from metastatic tumors compared to subject-matched cells from primary tumors. Knockdown of endogenous RPTP-β in HNSCC cells from primary tumor potentiated Met tyrosine phosphorylation, downstream mitogen-activated protein (MAP) kinase pathway activation, cell migration, and invasion. Conversely, restoration of RPTP-β expression in cells from matched metastatic tumor decreased Met tyrosine phosphorylation and downstream functions. Furthermore, we observed that six of eight HNSCC tumors had reduced levels of RPTP-β protein in comparison with normal oral tissues. Collectively, the results demonstrate the importance of RPTP-β in tumor biology of HNSCC through direct dephosphorylation of Met and regulation of downstream signal transduction pathways. Reduced RPTP-β levels, with or without Met overexpression, could promote Met activation in HNSCC tumors.