碳酸酐酶Ⅸ与肿瘤

碳酸酐酶（carbonic anhydrase，CA）是一族含锌酶，广泛存在于哺乳动物体内。CA至少有14种同工酶，其中CAⅨ位于VLH肿瘤抑制基因的下游，由HIF—I途径激活，在正常人体组织中主要位于胃肠道黏膜，而且表达较低，但在许多肿瘤如肾细胞癌、子宫颈癌和肺癌中表达明显增强，可能与肿瘤的发生发展密切相关。CAⅨ的表达水平可以预测肿瘤患者的预后情况，可以作为一种肿瘤特异抗原标志物应用于临床。肾细胞癌CAⅨ的高度特异性表达使其成为肿瘤疫苗潜在的靶抗原和肾癌治疗的重要靶位，在肾癌靶向治疗方面应用前景广阔。研究CAⅨ的表达和调控对于肿瘤的诊断和治疗具有重要意义。     

成纤维细胞与肿瘤相关性的研究进展

目的:总结国内外肿瘤相关成纤维细胞与肿瘤关系的研究进展。方法:检索PubMed及CNKI期刊全文数据库检索系统,以"肿瘤相关成纤维细胞(TAF)和肿瘤"等为关键词,检索2004-01-2011-10国内外TAF与肿瘤关系研究方面的文献,纳入标准:1)TAF的结构、功能、来源和表型的改变等;2)TAF与肿瘤的关系;3)TAF靶向治疗。根据纳入标准,最后纳入分析32篇文献。结果:TAF是肿瘤微环境中最主要的宿主细胞,它可能参与了肿瘤的发生,并且具有促进肿瘤细胞增殖、肿瘤血管生成、降低免疫监视和增加肿瘤的浸润侵袭的能力。结论:TAF在肿瘤的发生发展中可能起着重要的作用,通过TAF对肿瘤进行早期诊断以及以TAF为靶点进行治疗将会有很好的发展的前景。     

脂联素与肿瘤相关性的研究进展

脂肪组织已经不是普通意义上的脂肪仓库,而成为一个内分泌器官。脂肪细胞分泌的众多脂肪因子当中,脂联素(adiponectin)是惟一一个随着脂肪组织体积变大在血液循环中浓度反而降低的因子。脂联素不但在糖类和脂类代谢过程中起到重要作用,目前也认为和一些恶性肿瘤有关。大量的临床试验和基础研究表明,肿瘤患者血清脂联素水平偏低,并且肿瘤细胞表达脂联素受体。因此,脂联素可能通过与脂联素受体结合并激活受体和信号传导通路的下游,直接作用于肿瘤细胞,或者通过抗血管生成,诱导肿瘤细胞凋亡和其他机制调节细胞增殖,从而导致肿瘤的发生。通过研究脂联素,可以发现肥胖和肿瘤之间的关系。     

肿瘤与microRNA的DNA甲基化相关性研究进展

目的:总结国内外关于microRNA (miRNA)的DNA甲基化在各肿瘤中的研究进展.方法:应用PubMed及CNKI全文数据库检索系统,以“miRNA、DNA甲基化和肿瘤”为检索词,检索2004-04-2012-05的相关文献,共检索到英文文献401篇,中文文献40篇.文献纳入标准:1)miRNA的生物学特性;2)DNA甲基化的作用机制及与肿瘤的关系;3)miRNA的DNA甲基化与肿瘤发生发展的关系.根据纳入标准符合分析的文献27篇.结果:miRNA在肿瘤发生发展中可发挥癌基因和抑癌基因的作用,DNA甲基化是肿瘤发生的一个重要因素.20％受甲基化调控的miRNA在上游5 kb范围内有CpG岛,miRNA的DNA甲基化与CpG岛有密切关系.miR-34、miR-124、miR-9和miR-127的DNA甲基化在各种肿瘤中频繁发生,多数通过靶向调节癌基因或抑癌基因而在肿瘤发生发展中发挥作用.结论:miRNA的DNA甲基化在人类肿瘤中广泛存在,甲基化miRNA可能作为肿瘤早期诊断、治疗、转移和预后的分子标志.     

Girdin蛋白与肿瘤转移相关性的研究进展

目的:总结国内外对Girdin的结构及功能方面的研究进展。方法:应用Medline及维普数据库,以Girdin、actincytoskeleton和细胞迁移等为关键词,检索1996-01-2009-09的相关文献,共检索到英文文献786条,中文文献30条。纳入标准:1)Girdin的结构及相关功能的研究。2)细胞迁移所涉及的骨架结构的改变机制的研究。3)细胞迁移和侵袭相关内容的研究。根据纳入标准,精选35篇文献,最后纳入分析25篇文献。结果:Girdin(又被命名为APE、GIV、HkRP1)是一种新发现的肌动蛋白结合蛋白,它能与Akt相互作用,在调节肌动蛋白的结构及促进肿瘤细胞的运动等方面具有重要作用,但其详细机制还不明确。结论:Girdin作为抗肿瘤转移的新靶点,为指导肿瘤的临床治疗提供新的思路。     

紧密连接蛋白occludin与肿瘤相关性的研究进展

目的:总结occludin与肿瘤发生、发展和转移的研究进展。方法:应用Medline、PubMed及CNKI期刊全文数据库检索系统,以"occludin、信号传导、细胞转移和肿瘤"等为关键词,检索1998-01-2010-07的相关文献。纳入标准:1)occlu-din的一般特性;2)occludin与肿瘤分级、增殖和分化的关系;3)occludin与癌基因和抑癌基因;4)occludin与细胞信号传导;5)occludin与肿瘤的侵袭和转移。根据纳入标准,符合分析的文献38篇。结果:occludin是新近发现的一类黏附分子,能够介导上皮细胞及内皮细胞中紧密连接的形成。occludin的表达降低能够促进肿瘤的发生、发展及转移。结论:恶性肿瘤通过降低occludin的表达,使肿瘤细胞增殖、转移和侵袭能力大大加强,促进肿瘤的发展。occludin有可能为人类肿瘤的诊断和治疗方法提供新的科学依据,但是具体机制和方法尚待进一步研究。     

膜细胞骨架连接蛋白Ezrin与肿瘤侵袭转移相关性的研究现状

目的:总结膜细胞骨架连接蛋白Ezrin与肿瘤的侵袭转移之间关系的研究现状,探讨其在肿瘤转移中的重要作用及复杂机制.方法:应用pubMed及CNKI期刊全文数据库检索系统,以"Ezrin,埃兹蛋白,肿瘤"等为关键词,检索1999-2009年的相关文献,共检到文献486条.纳入标准:1)Ezrin促进肿瘤转移的机制.2)Ezrin抑制肿瘤转移的机制.3)Ezrin在不同肿瘤中的异常表达与预后.根据纳入标准,精选分析35篇文献.结果:Ezrin可以通过多种复杂的机制,在不同条件下发挥促进或是抑制肿瘤转移的作用.但是Ezrin在不同肿瘤中上调或下调的具体机制尚不清楚.它与其他肿瘤侵袭转移相关因子间的关系及信号转导机制也需进一步完善.结论:虽然Ezrin在肿瘤侵袭转移中的作用具有两面性,但其具体的调控机制和作用条件需要更加深入地研究和综合分析.     

淋巴管生成与胃肠道肿瘤转移关系的研究进展

淋巴管系统是恶性肿瘤转移的重要途径,但是人们对淋巴管生成在恶性肿瘤中的作用机制知之甚少。多种细胞因子参与了调节淋巴管生成的细胞信号传导通路,这些细胞因子包括：VEGF-C,VEGF-D,VEGFR-3,VEGF-A,FGF-2,Prox-1,Ang2和NP-2等;近年来发展起来的多种淋巴管内皮标志,如podoplanin、LYVE-1、Prox-1、VEGFR-3和LVEF等,为研究淋巴管生成在肿瘤中的作用提供了有力的工具;研究发现胃肠道肿瘤的淋巴管主要分布在肿瘤的周边区和正常区,肿瘤癌周组织的淋巴管密度明显高于正常组织的淋巴管密度;最近的研究还表明胃肠道恶性肿瘤的淋巴管生成与肿瘤的复发、转移和总生存率有一定的相关性。     

碳酸酐酶9及其在肾细胞癌防治中作用的研究进展

碳酸酐酶9（carbonic anhydrase IX，CA IX）是新发现的碳酸酐酶家族异构体之一，是由酸性氨基酸组成的跨膜糖蛋白，在调控细胞增殖、转化方面有重要作用。它能催化CO2水解为碳酸和水，参与机体的酸碱平衡，调节细胞内外pH值，有利于肿瘤的生长和转移。CA IX位于VHL肿瘤抑制基因的下游，由HIF-1途径激活，在正常组织中表达极低，在肾细胞癌中高度表达，是其特异性抗原。CA IX的表达水平可预测肾癌患者对白介素-2治疗的反应和生存期，CA IX低表达是不良预后因素。近年来对CA IX相应抗体的研究取得了很大进展，^131I标记的MAbG250在肾癌组织中具有高摄取率和高蓄积率，可对肾癌进行放射性核素显像，用来诊断肾癌；^131I标记的cG250MAb用于治疗晚期肾癌，已显示其安全性和有效性。肾细胞癌CA IX的高度特异性表达使其成为肿瘤疫苗潜在的靶抗原和肾癌治疗的重要靶位，在肾癌靶向治疗方面的应用前景广阔。     

肿瘤分子分期的应用前景

肿瘤的分子分期是当代肿瘤学的新概念，对肿瘤的预防、治疗、预后都较以往的临床分期具有更大的实用价值，随着分子分期的临床应用，肿瘤治疗学必将开始新的篇章。     

汗腺癌的研究及相关治疗进展

汗腺癌是一种罕见的具有侵袭性的恶性肿瘤,来源于皮肤真皮层及附属器的汗腺组织。多数发生于头颈部,四肢少见。临床特点是无症状的缓慢结节样生长。因其具有侵袭性,且局部淋巴结及远处转移为最常见的转移方式,因而依据组织病理学及免疫化学,汗腺癌需要与其他皮肤良性及恶性肿瘤鉴别。由于罕见及具有侵袭性,到目前为止,对于此病并无统一的治疗方案。局部广泛切除仍是首选的治疗手段,但由于其具有高度的局部复发性,50～70Gy 的放射治疗,或5-氟尿嘧啶和卡培他滨的联合化疗可以改善局部复发患者的预后。其他比如表皮生长因子阻滞剂,PI3K/ Akt/ mTOR 通路阻滞剂,雄激素抗体的激素治疗,电化学疗法等靶向治疗的研究正在进行临床实验。本文就汗腺癌的研究及相关治疗进展做一综述。     

乳腺癌相关分子病理学标志物研究进展

乳腺癌是女性发病率最高的恶性肿瘤，占女性恶性肿瘤的15％。乳腺癌分子病理学能够在基因和蛋白水平上检测瘤细胞的激素受体、生长因子、特异性蛋白、抑癌基因及癌基因等变化，并通过以上检查结果反映肿瘤细胞的分化、生长速度和转移侵袭性，为临床医师制定手术、放疗和化疗方案提供依据，提供有价值的预后信息和靶点治疗新思路。通过对这些生物标志物的阐述，可以更深入的认识乳腺癌的生物学行为。     

Hypoxia and cytokines regulate carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro

AIM: To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells.METHODS: We studied CA9 protein, CA9 mRNA and hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O₂) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation.RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1α protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-α and TGF-β, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1α protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-α and TGF-β, positively influence CA9 expression under both normoxic and hypoxic conditions.CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer.     

Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor

We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [¹¹¹In]XYIMSR-01 in 73.8–75.8% (n = 3) yield with specific radioactivities ranging from 118 – 1,021 GBq/μmol (3,200–27,600 Ci/mmol). Single photon emission computed tomography of [¹¹¹In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 ± 145.4, 68.4 ± 29.0 and 1.7 ± 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX.     

Function of carbonic anhydrase IX in glioblastoma multiforme

Carbonic anhydrase (CA) IX is over-expressed in glioblastoma; however, its functions in this context are unknown. Metabolically, glioblastomas are highly glycolytic, leading to a significant lactic acid load. Paradoxically, the intracellular pH is alkaline. We hypothesized that CAIX contributes to the extrusion of hydrogen ions into the extracellular space, thereby moderating intra- and extracellular pH and creating an environment conductive to enhanced invasion. We investigated the role of CAIX as a prognostic marker in patients with glioblastoma and its biological function in vitro. CAIX expression was analyzed in 59 patients with glioblastoma by immunohistochemistry. The expression levels were correlated to overall survival. In vitro, U251 and Ln 18 glioblastoma cells were incubated under hypoxia to induce CAIX expression, and RNA interference (RNAi) was used to examine the function of CAIX on cell attachment, invasion, intracellular energy transfer, and susceptibility to adjuvant treatment. High CAIX expression was identified as an independent factor for poor survival in patients with glioblastoma. In vitro, cell attachment and invasion were strongly reduced after knockdown of CAIX. Finally, the effects of radiation and chemotherapy were strongly augmented after CAIX interference and were accompanied by a higher rate of apoptotic cell death. CAIX is an independent prognostic factor for poor outcome in patients with glioblastoma. Cell attachment, invasion, and survival during adjuvant treatment are significantly influenced by high CAIX expression. These results indicate that inhibition of CAIX is a potential metabolic target for the treatment of patients with glioblastoma.     

Reserch progress of nasopharyngeal carcinoma related gene

The occurrence of nasopharyngeal carcinoma is a multi-gene, multi-step process. Among them, oncogene activation and antioncogene inactivation is the important mechanism. The related oncogenes of nasopharyngeal carcinoma contain Bcl-2, HGF, COX-2 and LMP-1. The related antioncogenes of nasopharyngeal carcinoma contain P53, P16, NM23-H1 and PTEN. With the deepening research on genes, studies also find that nasopharyngeal carcinoma is related to PECAM-1, MMP-9 and RECK. These genes play important roles in the occurrence and development of nasopharyngeal carcinoma, which may become new targets for the treatment of nasopharyngeal carcinoma.     

Detecting changes in tumor hypoxia with carbonic anhydrase IX and pimonidazole

We have used immunohistochemistry to examine the dynamics of tumor hypoxia.. Expression of CAIX is known to be influenced by tumor hypoxia, and this protein has been shown to be an endogenous hypoxia marker in several models. However, due to its long half-life, it could also be present in oxygenated tissue that had recently been hypoxic. To investigate this issue we have compared CAIX expression to the exogenous hypoxia marker, pimonidazole using HT29 (human colorectal cancer) xenografts. We manipulated tumor hypoxia with carbogen and hydralazine, treatments that respectively increased and decreased tumor oxygenation. (Carbogen was given 75 minutes and hydralazine 30 minutes before sacrifice). In tumors from the control group, CAIX and pimonidazole exhibited similar (though not identical) spatial distribution, and for both markers, the fraction of the section staining positively was similar (13.2% and 12.6% respectively). The mice treated with hydralazine showed a significant increase in pimonidazole accumulation (37.2%, p = 0.03), though the CAIX positive fraction was unchanged (14.2%). In contrast, in the carbogen group pimonidazole staining decreased to 3% (p = 0.01) though CAIX expression was again unaltered. These results suggest that comparison of CAIX and pimonidazole will allow for the detection of reoxygenation.     

鼻咽癌相关基因研究进展

鼻咽癌的发生是一个多基因参与、多步骤的复杂过程,其中抑癌基因失活和癌基因活化是其发生的重要机制.与鼻咽癌相关的癌基因有Bcl-2、肝细胞生长因子(HGF)、环氧合酶-2(COX-2)、潜伏膜蛋白1(LMP-1),抑癌基因有p53、p16、Nm23-H1、PTEN.随着基因研究的深入,除上述基因外,鼻咽癌还与PECAM-1、MMP-9、RECK等基因相关.这些基因在鼻咽癌的发生、发展过程中有重要作用并可能成为鼻咽癌治疗的新靶点.     

Stromal expression of carbonic anhydrase IX in esophageal cancer

Purpose

Carbonic anhydrase IX (CA IX), a transmembrane glycoprotein, is known as an endogenous marker for hypoxia. Overexpressed in cancer-associated fibroblasts, CA IX has been reported to be associated with a poor outcome for a number of malignant tumors. Aim of this study was to investigate the role of CA IX in the tumor surrounding stroma of esophageal cancer.

Methods/patients

Stromal expression of CA IX in 361 formalin-fixed, paraffin-embedded specimens of invasive esophageal cancers, 206 adenocarcinoma (AC) and 155 squamous cell carcinoma (SCC), was investigated.

Results

In 42 cases (11.6 %), CA IX expression in the tumor surrounding stroma (AC 23 and SCC 19) was observed. Expression of CA IX correlated with the factors tumor stage (p < 0.001) and lymph node status (p = 0.008). Patients with CA IX expressed in the tumor surrounding stroma had a significant shorter disease-free survival (p = 0.007) and overall survival (p = 0.013).

Conclusion

In esophageal cancer, CA IX-expressing tumor stroma is associated with shorter survival. Inhibition of the tyrosine kinase CA IX might represent a new onset for therapies against esophageal cancer.