骨桥蛋白与肿瘤治疗

骨桥蛋白(osteopontin,OPN)是一种分泌型磷酸化糖蛋白,由多种组织细胞合成与分泌,参与调节细胞的黏附、增殖、趋化、转移、浸润和凋亡过程。OPN在多种肿瘤中高表达,与肿瘤的发生和发展密切相关,组织和血液中的OPN表达量也是肿瘤诊断和预后的指标。近年来,越来越多的研究通过抑制OPN、OPN的受体以及OPN的下游信号通路的方法抑制了肿瘤的发展。本文将从多方面阐述OPN与肿瘤的关系以及与肿瘤治疗的研究进展。     

骨桥蛋白在肿瘤血管形成中的作用

骨桥蛋白(osteopontin OPN)是一种糖基化磷酸蛋白,许多肿瘤都可以分泌和表达.大量研究显示:OPN在恶性肿瘤转移播散过程中发挥重要作用.而新生血管形成是肿瘤转移进展过程中非常重要的步骤.OPN与肿瘤新生血管关系密切,癌组织中OPN的高表达与肿瘤微血管密度相关.OPN与许多血管形成因子相互影响协同促进血管形成.OPN通过与整合素和CD44受体结合的细胞信号通路作用于血管形成的重要参与者内皮细胞,影响其增殖,迁移,粘附,趋化,凋亡等生物学特性,并降解细胞外基质为内皮细胞在局部组织中延伸形成血管提供基础.最近的研究也显示OPN可以在血管干/祖细胞水平调节其增殖功能,从而影响肿瘤血管新生.本文将对OPN分子结构,OPN在肿瘤血管形成中所起的作用及相关机制进行综述.     

肿瘤干细胞与肿瘤转移

近年来,肿瘤干细胞(cancer stem cell,CSC)学说研究认为CSC与肿瘤发生、发展、转移和复发关系极为密切。研究还发现CSC具有明显的异质性,即CSC可分为增生、耐药、侵袭和转移等行为不同的亚群细胞,其中具有转移生物学特性的CSC亚群细胞称为肿瘤转移干细胞(migrating cancer stem cell,MCSC)。目前认为,上皮-间质转变、趋化因子和靶器官微环境可能在肿瘤转移过程中起着重要作用。针对MCSC及其相关机制的靶向治疗有望能更有效地遏制肿瘤的转移。     

尿激酶与肿瘤转移

尿激酶是一种丝氨酸蛋白水解酶,它能激活纤溶酶原成为纤溶酶,降解胞外基质,从而利于细胞迁移。肿瘤转移是导致肿瘤恶化和肿瘤病人死亡的主要原因之一。以尿激酶为中心,尿激酶受体介导的纤溶酶原激活系统在肿瘤转移过程中扮演了重要角色。     

nm23基因与肿瘤转移

ｎｍ２３基因位于人１７号染色的着丝点附近,其蛋白产物为１７ｋＤ的核苷二磷酸激酶,许多研究表明ｎｍ２３基因的表达水平和恶性肿瘤的转移有关,但也有与此相左的报道,本综述了ｎｍ２３基因的研究现状及其与肿瘤转移的关系。     

Stat3与肿瘤的侵袭转移

Stat3是信号传导与转录激活因子家族(STATs)的成员之一,是一种重要的核转录因子,被细胞外细胞因子、生长因子等多肽类配体激活,作用于细胞核内特异的DNA片段,调控靶基因的转录,促进肿瘤细胞的增殖、血管形成、侵袭转移及免疫逃逸。诸多肿瘤细胞系及人的癌变组织中存在Stat3持续激活,因而Stat3有可能成为肿瘤分子治疗的新靶点。     

肿瘤转移与细胞粘附

肿瘤转移与细胞粘附涂立宇,查锡良（上海医科大学生化教研室,上海２０００３２）关键词肿瘤转移,细胞粘附分子,胞外基质细胞粘附分子（ＣＡＭ）是指由细胞合成组装于细胞膜或分泌至胞外基质（ＥＣＭ）可促进细胞粘附的一大类分子。它们所介导的细胞－细胞和细胞－基质...     

间充质干细胞与肿瘤转移

间充质干细胞是一类能够自我更新、具有多向分化潜能的成体干细胞。近年来,有证据认为间充质干细胞是肿瘤组织中基质细胞的祖先,因此间充质干细胞微环境与肿瘤转移的关系逐渐成为研究热点,但间充质干细胞对肿瘤转移是促进还是抑制,目前的研究并不一致。我们简要综述了间充质干细胞参与肿瘤转移的研究进展。     

CD44与肿瘤转移

透明质酸受体CD44是一类重要的粘附分子,与肿瘤转移密切相关,。早期认为CD44可促进肿瘤细胞的转移,但近来发现CD44与肿瘤志移之间的关系十分复杂,与CD44的分子类型及肿瘤组织类型皆有关。因此,尚需深入了解CD44在肿瘤转移过程中的分子机制,目前的研究发现CD44可能影响了肿瘤细胞的粘附,运动和胞外基质的降解等过程,临床上CD44有可能成为新的诊断指标和治疗靶点。     

选择素与肿瘤转移研究进展

晚近发现的粘附分子受体（选择素）,能介导血小板、内皮细胞与中性粒细胞、单核细胞及肿瘤细胞的粘附,它们在炎症、血栓形成及肿瘤转移过程中起重要作用。本文练过了选择素的结构与功能特点,在正常组织中分布以及与肿瘤转移方面的有关研究进展。     

P-选凝素在肿瘤生长和转移中的作用

P-选凝素是细胞粘连分子家族的成员,表迭在活化的内皮细胞和血小板表面。P-选凝素能介导白细胞在激活的内皮细胞上滚动,还能介导白细胞和激活的血小板的聚集。另外P-选凝素可以介导肿瘤细胞和活化的血小板聚集,并帮助肿瘤细胞黏附到活化的内皮细胞表面。本文从肿瘤生物学角度综述了P-选凝素的表达和肿瘤相互关系的实验及临床研究。在临床上,P-选凝素作为肿瘤治疗的靶分子可能成为一种适宜于某些病人的选择性疗法。     

Osteopontin contributes to hepatocyte growth factor-induced tumor growth and metastasis formation

The cytokine hepatocyte growth factor (HGF)/scatter factor-1 and its cognate receptor, Met, are involved in the etiology and progression of many types of cancer. Despite recent advances in understanding the signal transduction pathways activated by HGF, the mechanism by which HGF exerts its tumorigenic effect is not well understood. To identify proteins that may be involved in mediating HGF-induced cell motility, invasiveness, and tumorigenesis, we used two separate differential display screening methods to identify changes in gene expression that are initiated by HGF in an epithelial cell culture system. Among several known and unknown genes whose expression was modified, osteopontin (OPN), a protein previously associated with tumorigenesis, was found to be upregulated within 6 h following HGF stimulation. OPN expression was dependent on activation of the PI-3 kinase pathway. Autocrine secretion of HGF resulted in sustained expression of OPN. Downregulation of opn expression by stable antisense transfection attenuated OPN expression and repressed HGF-induced invasiveness in vitro and decreased HGF-mediated tumor growth and metastasis formation in vivo. Constitutive expression of OPN in itself exerted partial invasiveness in vitro, but its expression itself was not sufficient to initiate tumor growth or metastasis formation in vivo. Thus, together with other molecules, OPN activity contributes to HGF-induced tumor growth and invasiveness.     

EMT参与肿瘤侵袭转移的研究进展

在癌症类型中,上皮癌占绝大多数。从良性腺瘤过渡到恶性癌和转移期间,上皮肿瘤细胞获得去分化、迁移和入侵行为,同时上皮-间质转化(epithelial-mesenchymal transition EMT)伴随着显著的细胞形态学变化、细胞与细胞间及细胞与基质之间的粘附性丢失及重塑、并获得迁徙和侵袭能力。正如完全分化的上皮细胞转换成低分化、迁移和侵入性间质细胞,其涉及到一个高度的细胞可塑性、大量不同的基因和表观遗传学改变,因此EMT本身是一个多阶段的过程。该综述的目的是系统地总结EMT分子机制及EMT与肿瘤关系的最新进展。     

EMT参与肿瘤侵袭转移的研究进展

在癌症类型中,上皮癌占绝大多数。从良性腺瘤过渡到恶性癌和转移期间,上皮肿瘤细胞获得去分化、迁移和入侵行为,同时上皮-间质转化（epithelial-mesenchymal transition EMT）伴随着显著的细胞形态学变化、细胞与细胞间及细胞与基质之间的粘附性丢失及重塑、并获得迁徙和侵袭能力。正如完全分化的上皮细胞转换成低分化、迁移和侵入性间质细胞,其涉及到一个高度的细胞可塑性、大量不同的基因和表观遗传学改变,因此EMT本身是一个多阶段的过程。该综述的目的是系统地总结EMT分子机制及EMT与肿瘤关系的最新进展。     

血源性兔VX2肿瘤脑及脑膜转移瘤动物模型的建立及MRI检测

目的：研究MRI对血源性脑及脑膜转移瘤动物模型转移灶的检出效果。方法：18只新西兰大白兔随机分为3组,分别从左颈总动脉内接种VX2瘤细胞,A组：20％甘露醇注入5min后接种VX2瘤细胞：B组：20％甘露醇注入5min后,加入肝素再接种VX2瘤细胞;C组,对照组,单纯注入等量生理盐水。术后2周后行MRI检查。病理取材HE染色光镜下观察。结果：平扫：A组,1只（1／6）发现脑内结节并脑膜结节样增厚,T1WI为等信号,T2WI为稍高信号。B组,2只（2／6）为脑内多发结节,T1WI为等信号,TM为稍高信号。2只（2／6）脑膜结节样增厚。增强扫描：A组,2只（2／6）脑内见强化结节灶;直径在1．5mm-7．0mm之间。4K（4／6）脑膜线样增厚或结节样增厚强化。B组,6只（6／6）脑内见直径在1．5mm-5．0mm的高信号结节,其中5只为脑内多发结节灶;4只（4／6）脑膜线样或结节样增厚强化,左侧为主,其中2只（2／6）为双侧脑膜增厚。增强扫描A、B组问脑内病灶差异有统计学意义（Fisher’s确切概率值为0．04）。C组平扫及增强扫描均未见异常信号。结论：上述方法制成的动物模型可为医学影像学研究提供可靠的动物模型,加入肝素可提高瘤灶的形成几率,并证实血脑屏障对脑转移瘤的形成起重要作用。MRI增强检查是检出脑内及脑膜转移瘤的首选方法。     

CPNE8 Promotes Gastric Cancer Metastasis by Modulating Focal Adhesion Pathway and Tumor Microenvironment

Little is known about the oncogenic role or biological function of copine Ⅷ (CPNE8) in gastric cancer (GC). Based on TCGA database, we screened for CPNE8 and analyzed the expression of CPNE8 in GC. The correlations between CPNE8 and clinical features were analyzed using TCGA and GEO databases. The prognostic value of CPNE8 was assessed using Cox analysis and Kaplan-Meier curves. The results showed that increased expression of CPNE8 was positively correlated with metastasis and can be considered an independent prognostic risk factor for poor survival. We found that CPNE8 can promote cell proliferation, migration, and invasiveness in GC using in vitro and in vivo experiments. Our study demonstrated that CPNE8 promotes tumor progression via regulation of focal adhesion, and these effects can be rescued by focal adhesion kinase (FAK) inhibitor GSK2256098 or knockdown of FAK. In addition, CPNE8 was correlated significantly with the infiltration of cancer-associated fibroblasts and immune cells, as demonstrated by various algorithms, and high CPNE8 expression predicted poor efficacy of immune checkpoint therapy. Our findings suggest that CPNE8 modulates focal adhesion and tumor microenvironment to promote GC progression and invasiveness and could serve as a novel prognostic biomarker in GC.     

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Osteopontin (OPN) is a secreted phosphoprotein, originally characterized in malignant-transformed epithelial cells. OPN is associated with tumor metastasis of several tumors and is overexpressed in hepatocellular carcinoma (HCC) tissue involving HCC invasion and metastasis. Importantly, OPN is significantly up-regulated in liver injury, inflammation, and hepatitis C virus (HCV)-associated HCC. However, the underlying mechanisms of OPN activation and its role in HCV-mediated liver disease pathogenesis are not known. In this study, we investigated the mechanism of OPN activation in HCV-infected cells. We demonstrate that HCV-mediated Ca²⁺ signaling, elevation of reactive oxygen species, and activation of cellular kinases such as p38 MAPK, JNK, PI3K, and MEK1/2 are involved in OPN activation. Incubation of HCV-infected cells with the inhibitors of AP-1 and Sp1 and site-directed mutagenesis of AP-1- and Sp1-binding sites on the OPN promoter suggest the critical role of AP-1 and Sp1 in OPN promoter activation. In addition, we show the in vivo interactions of AP-1 and Sp1 with the OPN promoter using chromatin immunoprecipitation assay. We also show the calpain-mediated processing of precursor OPN (∼75 kDa) into ∼55-, ∼42-, and ∼36-kDa forms of OPN in HCV-infected cells. Furthermore, we demonstrate the critical role of HCV-induced OPN in increased phosphorylation of Akt and GSK-3β followed by the activation of β-catenin, which can lead to EMT of hepatocytes. Taken together, these studies provide an insight into the mechanisms of OPN activation that is relevant to the metastasis of HCV-associated HCC.     

Osteopontin is upregulated by BCR-ABL

Chronic myelogenous leukemia (CML) is characterized by its hallmark oncogene BCR-ABL and the progression from a chronic phase toward an acute leukemia, with a differentiation arrest of the leukemic clone. In the present study, we conducted a microarray analysis using an inducible model of BCR-ABL expression based on the TET-OFF system, and we found that osteopontin (OPN), a component of stem cell niche, is overexpressed in BCR-ABL-expressing cells. Studies using mutant forms of BCR-ABL demonstrated that the BCR-ABL-induced OPN overexpression was a tyrosine kinase-dependent event. Furthermore, OPN concentration was significantly increased in the serum of leukemic mice generated by transplantation of BCR-ABL-expressing bone marrow cells. Most importantly, a significant increase of OPN concentration was observed in the serum of CML patients as compared to controls. Overall these results show that OPN is deregulated by BCR-ABL oncogene and suggest that OPN could be involved in CML stem cell biology.     

Disruption of Lysosome Function Promotes Tumor Growth and Metastasis in Drosophila

Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras^V12 cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras^V12 cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras^V12 cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.