c-Met及HGF在胃癌及其肝转移灶中的表达

目的:探讨胃癌肝细胞生长因子受体(c-Met)及肝细胞生长因子(HGF)表达与胃癌肝转移间的相关性。方法:晚期胃癌标本59例,其中11例同时有取自左肝外叶的肝转移标本,应用免疫组化方法对上述组织石蜡标本进行检测。结果:59例胃癌中,c-Met阳性率55.8%(33/59),HGF阳性率28.8%(17/59);在29例发生了同时或异时性肝转移的胃癌标本中,c-Met表达率为75.9%(22/29),HGF阳性率为37.9%(11/29),其中c-Met表达率在有和无肝转移组间有显著差异(P<0.05);在11例胃癌肝转移灶中,9例c-Met阳性表达率为81.8%,3例HGF阳性表达率为27.3%。结论:胃癌组织c-Met表达可能与胃癌肝转移行为相关。     

Immunoblot analysis of c-Met expression in human colorectal cancer: Overexpression is associated with advanced stage cancer

c-Met, the receptor of hepatocyte growth factor is known to be responsible for the motility and mitogenesis of epithelial cells including cancer cells. To investigate the significance of c-Met expression in human colorectal cancer (CRC), total cellular protein, extracted from 130 CRCs were examined by Western blot analysis. The signal was quantitated by ChemiImager™ 4000 Low Light Imaging System. c-Met expression was analyzed as the ratio of tumor to matched normal tissue (T/N) and expressed as fold-increase. The cellular localization of c-Met was assessed by immunohistochemistry. The T/N fold increase of c-Met varied from 0.2 to 10.7 with a mean of 3.41 ± 0.23 (mean ± SE). 69% primary CRC showed overexpression (T/N >2.0) of c-Met. Significantly higher c-Met levels were found in CRC with blood vessel invasion (P = 0.04), and in advanced stage (P = 0.04). No relationship was noted between c-Met expression and age, tumor size, location, differentiation. C-Met immunoreactivity was observed in the membrane and cytoplasm of cancer cells. Positive staining of endothelial cells of blood vessels within normal submucosa and tumor was also evident. C-Met protein is expressed at levels significantly higher than adjacent mucosa in most primary adenocarcinomas of the colon. Our results support an important role for c-Met in human CRC progression and metastasis.     

肝细胞生长因子及其受体在肿瘤中的研究进展

肝细胞生长因子是一种多肽生长因子,与其受体结合后,具有强促分裂、组织成形、诱导肿瘤细胞迁移、侵袭以及诱导血管生成等作用。肝细胞生长因子受体c-Met广泛存在于多种正常组织细胞和体内外恶性肿瘤细胞内,肝细胞生长因子与其受体和肿瘤的发生、发展以及肿瘤新生血管形成有密切关系。     

肝细胞生长因子与急性肾衰竭

肝细胞生长因子 (HGF)是一种高效的多效性因子 ,对多种器官的不同类型细胞均有多种生物学作用。HGF对于肾脏的发生、形成、修复及肾脏病理过程有重要作用 ,在急性肾衰竭 (ARF)时HGF具有促进肾小管修复及肾脏再生 ,降低死亡率 ,缩短病程的作用 ;在各种慢性肾脏疾病的发生发展中具有重要的调节作用。     

细胞因子HGF体外增强骨肉瘤细胞株的增殖和黏附性

【目的】研究肝细胞生长因子，离散因子（HGF／SF）及其受体蛋白c-Met在骨肉瘤细胞株MG-63和HOS中的表达及对瘤细胞生物学行为的影响，探讨HGF／c-Met系统在骨肉瘤细胞生长侵袭过程中的作用。【方法】用流式细胞术检测HGF-α、HGF-β、c-Met在2株骨肉瘤细胞株中的表达；外源性HGF刺激此2株细胞株后，用MTT法、黏附性检测方法研究细胞增殖速率和黏附性的变化。【结果】HGF-α、HGF-β、c-Met在2株骨肉瘤细胞株中的阳性表达率均低于3％。HGF浓度达50ng／mL以上时．MG-63和HOS的增殖速率显著增高，P〈0．01。当外源性HGF的浓度分别达5ng／mL和10ng／mL时，MG-63和HOS的黏附性指标即显著升高，P〈0．01。外源性HGF刺激后HGF-α、HGF-β、c-Met在2株骨肉瘤细胞株中的表达略有变化，但差异无统计学意义，P〉0．05。【结论】HGF可以促进骨肉瘤细胞株MG-63和HOS的体外增殖和黏附能力。     

Brief overview of selected approaches in targeting pancreatic adenocarcinoma

Introduction: Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, with 5-year survival painfully inadequate at under 5%. Investigators have struggled to target and exploit PDAC unique biology, failing to bring meaningful results from bench to bedside. Nonetheless, in recent years, several promising targets have emerged.

Areas covered: This review will discuss novel drug approaches in development for use in PDAC. The authors examine the continued efforts to target Kirsten rat sarcoma viral oncogene homolog (KRas), which have recently been successfully abated using novel small interfering RNA (siRNA) eluting devices. The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase.

Expert opinion: Although studies into novel biomarkers and advanced imaging have highlighted the potential new avenues toward discovering localized tumors earlier, the current therapeutic options highlight the fact that PDAC is a highly metastatic and chemoresistant cancer that often must be fought with virulent, systemic therapies. Several newer approaches, including siRNA targeting of mutated KRas and enzymatic depletion of hyaluronan with PEGylated hyaluronidase are particularly exciting given their early stage results. Further research should help in elucidating their potential impact as therapeutic options.     

Lysophosphatidic acid transactivates both c-Met and epidermal growth factor receptor, and induces cyclooxygenase-2 expression in human colon cancer LoVo cells

AIM: To examine whether lysophosphatidic acid (LPA) induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells. METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS: Immunoprecipitation analysis revealed that 10 umol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 umol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2, and thus may act as a potent stimulator of colorectal cancer.     

The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity

Acetaminophen (APAP)-induced hepatotoxicity comes among the most frequent humans’ toxicities caused by drugs. So far, therapeutic interventions for such type of drug-induced toxicity are still limited. In the current study, we examined the influence of capmatinib (Cap), a novel c-Met inhibitor, on APAP-induced hepatotoxicity in mice when administered 2 h prior, 2 h post and 4 h post APAP-challenge. The results revealed that Cap administration significantly attenuated APAP-induced liver injury when administered only 2 h prior and post APAP-administration. Cap hepatoprotective effect was mediated by lowering the excessive formation of lipid peroxidation and nitrosative stress products caused by APAP. Besides, Cap attenuated APAP-induced overproduction and release of proinflammatory mediators like TNF-α, IL-1β, IL-17A, IL-6, and MCP-1. Cap treatment also led to avoidance of APAP-subsequent repair by abating APAP-induced elevation of hepatic IL-22 and PCNA expressions. In conclusion, c-Met receptor inhibition may be a potential strategy for alleviating APAP-hepatotoxicity, especially when administered in the early phase of intoxication.