整合素ανβ3在肿瘤中的研究进展

整合素是细胞表面重要的黏附分子,介导细胞与胞外基质的相互作用,在肿瘤的发生、侵袭、转移以及肿瘤血管的形成过程中发挥重要的作用.随着对整合素的深入了解,很多整合素分子在肿瘤中的作用也被逐渐地认识,目前采用针对整合素不同分子的克隆抗体、整合素靶向用药及多种方法联合治疗等,通过调节整合素的生物学作用,促进肿瘤细胞凋亡,阻断肿瘤细胞侵袭迁移,抑制肿瘤血管的生成,从而达到治疗肿瘤的目的 .这些研究发现对开拓肿瘤治疗新方案有着重要的意义.     

整合素与肿瘤侵袭及转移的关系

肿瘤细胞与细胞外基质间的相互作用影响肿瘤的发生、增殖、存活和转移到其他组织的能力。许多是由分布广泛的整合素介导的。整合素是细胞黏附、细胞迁移、细胞周期和程序化死亡 (凋亡 )所必须的 ,它和其他信号途径一起调节肿瘤的发生、侵袭及转移。就整合素的结构、功能及其与肿瘤临床资料的关系予以综述     

肝细胞生长因子受体在肿瘤中的研究进展

肝细胞生长因子受体c-Met属酪氨酸激酶受体,当HGF与c-Met结合后,会导致一系列信号途径的激活,最终引起肿瘤细胞的增殖、侵袭和转移。本文就c-Met对多种恶性肿瘤的影响及c-Met引起肿瘤的作用机制进行简要综述。     

整合素与肿瘤侵袭及转移的关系

肿瘤细胞与细胞外基质间的相互作用影响肿瘤的发生、增殖、存活和转移到其他组织的能力。许多是由分布广泛的整合素介导的。整合素是细胞黏附．细胞迁移、细胞周期和程序化死亡(凋亡)所必须的，它和其他信号途径一起调节肿瘤的发生、侵袭及转移。就整合素的结构、功能及其与肿瘤临床资料的关系予以综述。     

整合素与肿瘤

 整合素是一类重要的细胞表面受体，其配体主要为细胞外基质（EMC）蛋白，如：胶原蛋白、纤粘连蛋白、层粘连蛋白等，整合素通过识别这些胞外基质蛋白介导细胞与细胞外基质、细胞与细胞间的粘附反应并接受、传导级联信号以及调节细胞的存活、运动、增殖等生物学过程，在胚胎发育、肿瘤发生和侵袭转移、炎症、伤口愈合等过程中起了重要的作用。自1987年，Hynes提出整合素以来，对整合素所涉及的细胞粘附、运动行为在肿瘤发生和转移、细胞增殖、淋巴细胞归巢、细胞凋亡、信号传导等机制方面所参与的环节、作用愈来愈被人们所认识[1,2]。目前，在癌症研究方面，对整合素的研究已突破了长期以来认为其仅起细胞粘附作用的认识，对整合素在肿瘤形成、生长、侵袭和转移、细胞凋亡等过程中所起的作用以及信号传导机制已受到广泛的关注。因此，本文在此就整合素与肿瘤的关系作一介绍。     

整合素αvβ6在卵巢癌中的作用

整合素是一类介导细胞与细胞外基质及细胞与细胞间黏附的细胞黏附分子受体，αvβ6是整合素家族的一员，参与肿瘤的发生、发展与转移。这种作用可能是通过影响肿瘤细胞与细胞外基质黏附、细胞外基质水解、诱导肿瘤血管生成、调节肿瘤细胞凋亡等作用而实现的。深入研究αvβ6在卵巢癌中的表达与功能，有助于进一步认识卵巢癌侵袭转移的分子机制，有可能为恶性肿瘤的诊断和预后判断提供新的指标．为开发肿瘤治疗新思路提供了理论依据。     

与肿瘤转移相关的上皮间质转化信号通路研究进展

恶性肿瘤细胞的侵袭和转移是患者死亡的主要原因,而上皮间质转化（epithelial　mesenchymal　transition,EMT）是肿瘤细胞侵袭和迁移的关键步骤。肿瘤细胞发生上皮间质转化可通过多种信号通路介导产生,深入了解与EMT相关的信号通路,可在信号通路中设立靶点,中止EMT的发生,进而阻止肿瘤侵袭、转移。本文就与肿瘤转移相关的EMT信号通路研究进展作一综述。     

整合素和胰腺癌侵袭转移

肿瘤侵袭转移是一个多因素共同作用的多阶段连续过程，其中肿瘤细胞与细胞外基质(extracellular matrix，ECM)的黏附是发生侵袭转移的首要步骤。近年来研究表明，整合素(integrins)黏附分子作为ECM的受体，通过介导细胞与细胞、细胞与ECM间的识别和结合，在肿瘤侵袭转移过程中起着极其重要的作用。     

整合素家族与肿瘤骨转移相关性研究进展

整合素家族作为黏附分子,主要介导细胞与细胞外基质间的黏附,调节许多类型肿瘤细胞的迁移、存活、增殖和血管生成等。近期许多研究证实,整合素家族还和恶性肿瘤的骨转移有着密切的关系。本文就整合素家族结构与功能、整合素家族信号通路与肿瘤转移关系、整合素与肿瘤骨转移的形成等方面进行综述。     

整合素家族与肿瘤骨转移相关性研究进展

整合素家族作为黏附分子,主要介导细胞与细胞外基质间的黏附,调节许多类型肿瘤细胞的迁移、存活、增殖和血管生成等。近期许多研究证实,整合素家族还和恶性肿瘤的骨转移有着密切的关系。本文就整合素家族结构与功能、整合素家族信号通路与肿瘤转移关系、整合素与肿瘤骨转移的形成等方面进行综述。     

Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors

Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met. SIGNIFICANCE: This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis.     

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrin-mediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.     

HGF/c-Met通路及其与肝癌和胆管癌的相关研究

肝细胞生长因子及其受体(HGF/c-Met)通路的过度激活在肿瘤的演进过程中起到非常重要的作用.研究证实HGF/c-Met在肝癌及胆管癌中呈高表达,直接或间接参与肿瘤的发生、侵袭和转移过程,且与预后有重要关系.近年来,针对该通路抑制剂的研发已成为抗肿瘤药物的研究热点.     

NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics

Invasion and subsequent establishment of metastasis are devastating events for patients with cancer, but past therapeutic approaches have paid relatively little attention to these important issues. Hepatocyte growth factor (HGF) and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Activation of the c-Met receptor integrates multiple signal transduction pathways involved in cell-cell and cell-matrix interactions, cellular migration, and breakdown of the extracellular scaffold. Paracrine activation of the c-Met receptor by stromal-derived HGF mediates tumor-stromal interactions that facilitate invasion and metastasis. Likewise, aberrant expression of the c-Met receptor and autocrine or mutational activation of c-Met receptor tyrosine kinase are closely associated with the progression of malignant tumors. Based on this background, NK4, a competitive antagonist of HGF-c-Met association was prepared so as to block cancer invasion and metastasis. NK4, an internal fragment of HGF, binds to but does not activate the c-Met receptor, thereby competitively antagonizing the biological activities of HGF. Unexpectedly, NK4 was subsequently shown to be an angiogenesis inhibitor as well, and this angioinhibitory activity is independent of its action as an HGF-antagonist. Importantly, NK4 protein or NK4 gene therapy have been shown to inhibit tumor invasion, metastasis and angiogenesis, effectively converting malignant tumors into benign tumors. Targeting tumor invasion-metastasis and angiogenesis with NK4 seems to have considerable therapeutic potential for cancer patients. (Cancer Sci 2003; 94: 321–327)     

Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model.

PURPOSE: The expression of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, frequently increases during prostate tumor progression. However, whether reduced c-Met expression inhibits tumor growth and metastasis has not been ascertained. EXPERIMENTAL DESIGN: c-Met expression was reduced by infection of an adenovirus expressing a c-Met ribozyme into the highly metastatic human prostate cancer cell line PC3-LN4. In vitro, effects on c-Met, Akt, and extracellular signal-regulated kinase 1/2 expression and phosphorylation, Src expression and activity, and vascular endothelial growth factor expression were determined, as were effects on cell migration and invasion. Prostate tumor formation and metastasis to regional lymph nodes in nude mice were examined after both ex vivo and in vivo infection of cells. RESULTS: Infection of PC3-LN4 cells with the Ad-c-Met-expressing ribozyme decreased steady-state c-Met levels, decreased Src kinase activity, decreased vascular endothelial growth factor expression, and decreased migration and invasion versus the pU1 (control) virus. Significant inhibition of tumorigenicity (histologically confirmed tumors in only 1 of 10 mice) and consequent lymph node metastasis were observed upon ex vivo infection of Ad-c-Met. Similarly, gene therapy experiments led to complete inhibition of tumor growth in 7 of 8 mice. CONCLUSIONS: Reduction in c-Met expression substantially inhibits both tumor growth and lymph node metastasis of PC3-LN4 cells in orthotopic nude mouse models. Therefore, targeting the c-Met signaling pathways may be important in controlling tumor growth and metastasis in human prostate cancers.     

Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis

The role of the fibronectin receptor, α(5)β(1)-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α(5)β(1)-integrin led to a direct association of α(5)-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α(5)β(1)-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α(5)β(1)-integrin inhibition on tumor cell invasion, indicating that α(5)β(1)-integrin is upstream of c-Met, Src and FAK. Inhibition of α(5)β(1)-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α(5)β(1)-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α(5)β(1)-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.     

Hepatocyte growth factor and c-Met immunoreactivity are associated with metastasis in high grade salivary gland carcinoma

Interactions between hepatocyte growth factor (HGF) and its receptor, c-Met, have been associated with invasion, metastasis and carcinogenesis in in vitro experiments. We investigated the relationship between HGF/c-Met immunoreactivity and the clinical features of 33 patients with high grade salivary gland carcinomas. c-Met and stromal HGF (expression of HGF in fibroblasts adjacent to tumor nests) were found to significantly correlate with regional lymph node and distant metastasis (p<0.05), but not with HGF expression, in tumor cells. Stromal HGF was also found to correlate with tumor size (p<0.05). In addition, a significant correlation between c-Met and stromal HGF expression (p<0.0001) was observed. Overall survival in patients with c-Met and stromal HGF immunoreactivity was significantly worse than in patients without c-Met and stromal HGF immunoreactivity (p=0.0002). The present findings suggest that HGF may bind to c-Met in a paracrine fashion, thereby enabling metastasis of high grade salivary gland carcinomas. Thus, HGF/c-Met immunoreactivity might be associated with a poor prognosis in patients with high grade salivary gland carcinomas.     

HGF/c-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis

Recent studies in several tumor models indicated that treatment with angiogenic inhibitors may trigger induction of metastasis to other organs. Here we investigated modes of resistance and invasion in several tumor cell lines including 4T1 (breast), H460 (lung) and Colo205 (colorectal) using sunitinib at doses comparable to clinically utilized regimen. In comparison with vehicle-treated tumors, sunitinib increased metastasis to lung in 4T1 tumors and to peritoneal lymph node in Colo205 tumors. However, the same treatment did not induce invasiveness in H460 tumors, further suggesting that accelerating metastasis during treatment with angiogenic inhibitors is tumor cell-type dependent. Interestingly, Crizotinib (a dual inhibitor of c-Met and ALK pathways) as single agent or in combination with sunitinib reduced metastasis in all models tested suggesting a role for c-Met/HGF pathway in intrinsic- or sunitinib-induced-metastasis. Moreover, ELISA data showed that while c-Met is highly enriched in tumor cells, HGF is secreted mainly by the stroma (mouse HGF) suggesting a paracrine fashion for c-Met pathway activation in the tumors. In conclusion, our findings indicate that sunitinib-induced metastasis is tumor cell-type dependent and further supports a rationale for combination of anti-angiogenics and c-Met inhibition in the clinic.     

Human papillomavirus type 16 E6 protein inhibits DNA fragmentation via interaction with DNA fragmentation factor 40

Aquaporin 3 (AQP3) and c-Met are both overexpressed in human gastric carcinoma and highly associated with its metastasis and invasion. However, it still remains unknown whether c-Met and AQP3 correlate with each other. Herein, we demonstrated that c-Met expression in gastric cancer tissues significantly correlated with differentiation, lymph node metastasis and lymphovascular invasion, and c-Met exhibited marked association with AQP3 expression. Immunoblotting assays showed that hHGF phosphorylated c-Met in SGC7901 and AGS cells and upregulated AQP3 expression in a dose- or time-dependent way. RNAi against c-Met reduced total c-Met levels by about two thirds in both AGS and SGC7901 cells and attenuated hHGF-induced AQP3 expression significantly. In vitro migration and proliferation assays showed that siRNA against AQP3 noticeably restrained HGF-promoted migration and proliferation of these cells. Furthermore, Immunoblotting studies revealed that HGF induced phosphorylation of ERK, and pre-treatment with U0126, a MAPK/ERK inhibitor, partially inhibited hHGF-induced increase in AQP3 expression. Together, these data provide initial evidence that c-Met regulates the expression of AQP3 via the ERK signalling pathway in gastric carcinoma. These findings assist in understanding the mechanism of growth and invasion of gastric carcinoma, and provide a possible strategy for the inhibition of gastric tumor metastasis.     

结肠癌转移相关基因1及其在肿瘤中的作用

结肠癌转移相关基因1(MACC1)编码的蛋白质在肝细胞生长因子/肝细胞生长因子受体(HGF/c-Met)信号转导通路中转录激活c-Met基因,上调c-Met蛋白的表达,促进肿瘤细胞的侵袭和转移.MACC1蛋白高表达与人类多种肿瘤的发生和转移相关,如结肠癌、胃癌、肝癌、肺癌、卵巢癌等,且与肿瘤临床分期、有无远处转移密切相关,可作为肿瘤转移和预后判断的独立指标,为基因治疗提供新靶点.