细菌生物膜：结直肠癌发生发展的重要参与者

摘 要：结直肠癌的发病与许多危险因素有关，最近的研究表明细菌生物膜可能在结直肠癌发病过程中发挥着重要作用。生物膜是指附着在生物或非生物表面聚合物基质中的微生物群落聚合体，生物膜的形成可能通过增强细菌介导的基因毒性、增高宿主体内致癌代谢物及调节免疫炎症反应等机制促进结直肠癌发生及发展，细菌生物膜可以认为是健康和疾病的肠道之间的临界点。全文就近年来国内外关于细菌生物膜与结肠癌发生、发展研究的有关热点问题进行概述，为细菌生物膜相关研究和结肠癌的预防、诊断及治疗提供理论参考。     

细菌致癌促癌机制的研究进展

通常认为肿瘤发生来源于癌基因与抑癌基因的突变,肿瘤的发展与机体炎症反应、免疫状态、肿瘤微环境等密不可分。然而近年来,随着宏基因组学和生物信息学的不断发展进步,越来越多研究证实,细菌对肿瘤的发生发展具有重要作用。细菌可以通过自身及其产物直接作用促进肿瘤发生,也可通过影响宿主代谢、诱发炎症反应、抑制肿瘤免疫等间接方式参与肿瘤发展。本文将对细菌致癌促癌机制做简要综述。     

血管紧张素Ⅱ用于增强肿瘤化疗

现有抗癌药物的作用缺乏选择性,在杀灭癌细胞的同时对机体的正常组织如骨髓、胃肠道等也具有不同程度的损害作用。这不但降低了药物的安全性,也影响了其疗效的充分发挥。尤其是当肿瘤进入晚期,抗癌药物对宿主的毒性趋于增加,必须减量用药。显然,增强抗癌药物对肿瘤的选择性作用具有重要意义。近年来为研究增强药物对癌细胞的杀伤作用的选择性或选择性地保护正常组织细胞的方法做了不少工作。本文讨论用血管     

癌症的基因治疗

癌症基因治疗进展很快,概括起来主要有:用基因治疗来增强宿主抗癌免疫、恢复抗癌基因功能、阻止癌基因的表达、逆转肿瘤的恶性表型,优化抗癌药物的效用和转移多药抗性等,现将癌基因治疗情况做一全面综述。 1 基因疗法和基因治疗的现状 1.1 用重组DNA构建表达细胞因子和淋巴因子的免疫治疗 IL—2能通过增强人体免疫反应来使肿瘤消退。然而,除恶性黑色素瘤和肾癌病人外,癌症病人     

细菌在肿瘤治疗中的应用——从基础到临床

目前,肿瘤治疗方法日趋多样,其中细菌治疗渐成近年来的研究热点。细菌治疗肿瘤主要基于其独特的作用机制能触发宿主抗肿瘤免疫作用,以及部分细菌能靶向性定植于肿瘤内部的特点,在实体肿瘤的基础研究和临床研究中均取得令人鼓舞的疗效。综述就工程化细菌在肿瘤免疫治疗中的具体策略以及一些临床试验研究进行整理,讨论细菌疗法目前所面临的挑战及应对策略等,以期为进一步的研究奠定基础,推进细菌在肿瘤治疗中的临床应用。     

肿瘤发生与免疫逃逸相关机制的研究进展

摘 要：肿瘤免疫逃逸是肿瘤细胞逃避宿主免疫系统监视和攻击,促进肿瘤生存和增殖的重要途径。此外,肿瘤细胞内异常表达的PI3K-AKT、MAPK等信号通路增强了其增殖、侵袭、转移、抗凋亡等能力,从而在与宿主免疫系统的抗争中处于有利地位。通过对肿瘤与免疫逃逸相关机制的研究,有利于包括免疫治疗在内的各种肿瘤治疗方法的发展。     

细菌生物膜参与结直肠癌发生的作用机制

结直肠癌是最常见的恶性肿瘤之一,发病率呈逐年上升趋势。肠道是人体内微生物定植量最高的器官,肠道菌群失衡在结直肠癌的发生发展中发挥了重要作用。肠道细菌生物膜（bacterial biofilm, BF）是由多种肠道细菌有组织生长形成的聚集体。生物膜的形成大大增加了肠道细菌对抗生素等杀菌剂和宿主免疫防御的抵抗力。最新的观点认为在肠道菌群诱导结直肠上皮细胞发生癌变的过程中,细菌生物膜的形成是一项至关重要的中间环节。本文结合最近国内外的研究现状对细菌生物膜促进肠道上皮细胞发生致癌转化作一简要综述。     

伤寒沙门菌在肿瘤治疗中的研究

随着肿瘤特异性靶向菌株的发现和生物技术的发展,伤寒沙门菌以其兼性厌氧、胞内寄生并通过Ⅲ型分泌机制作用于宿主细胞使细菌的效应蛋白直接转移到真核细胞、增强机体的免疫等生物学特点,为肿瘤治疗提供了靶向治疗新策略.     

肠道菌群对肿瘤放疗的影响

肠道微生物群具有多种生理功能,在宿主健康和肠道内环境稳定中起着关键作用。肿瘤的放疗会导致肠道菌群紊乱、免疫失调,引起急慢性炎症。同时,肠道菌群及其代谢物会影响放疗的效果和不良反应发生。现已发现应用益生菌、抗生素、粪便移植、菌群代谢物等改变宿主肠道菌群的方法具有预防和治疗放射性肠炎、增加放射敏感性及增强放疗效果的作用。文章就肠道菌群对肿瘤放疗的影响进行综述。     

光动力疗法联合相关治疗研究进展

目的:总结可增强光动力疗法(PDT)抗肿瘤免疫效应的相关治疗研究进展.方法:应用PubMed和CNKI数据库,以“光动力疗法、肿瘤、免疫疗法、靶向光敏剂、肿瘤疫苗和免疫抑制”等为关键词,检索2000-01—2011-08的相关文献.纳入标准:1)PDT联合的免疫疗法;2)靶向光敏剂;3)PDT光照剂量;4)PDT免疫抑制效应; 5)PDT肿瘤疫苗.排除重复研究与本研究无关的文献,符合分析的文献32篇.结果:PDT处理后对宿主免疫系统的影响极为复杂,既能促进抗肿瘤免疫,在某些情况下又能抑制免疫;PDT联合免疫佐剂、细胞因子或免疫细胞可有效增强PDT抗肿瘤免疫反应;疫抑制效应具有条件性,可通过制备靶向光敏剂、调节光照剂量和去除负向调节性免疫效应分子及调节性T细胞等多种途径减弱甚至去除这种生物效应;PDT处理后肿瘤细胞裂解物具有免疫刺激作用,可用作肿瘤疫苗.结论:联合免疫疗法或其他方法来增强PDT抗肿瘤免疫效应、拮抗免疫抑制效应,可显著提高PDT抗肿瘤疗效.     

利用低氧的厌氧菌抗肿瘤治疗

实体瘤低氧区无法获得抗癌药且对放疗耐受,但却为厌氧菌的生长提供了良好的环境。利用厌氧菌趋低氧的特性靶向并破坏肿瘤低氧区,既可作为基因治疗的肿瘤特异载体又可以联合其他治疗增强其抗肿瘤效应。基于厌氧菌的细菌溶瘤治疗具有广阔的前景。     

Tumor-selective Blood Flow Decrease Induced by an Angiotensin Converting Enzyme Inhibitor, Temocapril Hydrochloride

To enhance chemotherapeutic efficacy against cancer, it is important to deliver anticancer drugs preferentially to cancer cells and to retain the drugs there for a prolonged time. The in vivo prolongation of the exposure time of anticancer drugs in tumors can be accomplished by decreasing tumor tissue blood flow (tBF) after anticancer drug administration. The present study demonstrated that temocapril hydrochloride, an angiotensin converting enzyme inhibitor, decreases tumor tBF markedly in LY80 tumor, a subline of Yoshida sarcoma in the rat, without affecting the blood flow in liver, kidney, bone marrow, and brain. In tumor areas with flow of above 20 ml/min/ 100 g, the tBF decreased by approximately 50% due to temocapril. In tumor areas with tBF of about 20 ml/min/100 g, it became less than 3 ml/min/100 g with temocapril and did not recover during the 2 h experiment. These findings were obtained not only in large tumors, but also in microfoci growing within a transparent chamber. Furthermore, even when temocapril was administered under the condition of increased tumor tBF by administering angiotensin II, tumor tBF decreased immediately. Using this technique, it should be possible to trap anticancer drugs selectively in tumor tissue for an extended period of time.     

Tumor-selective blood flow decrease induced by an angiotensin converting enzyme inhibitor, temocapril hydrochloride.

To enhance chemotherapeutic efficacy against cancer, it is important to deliver anticancer drugs preferentially to cancer cells and to retain the drugs there for a prolonged time. The in vivo prolongation of the exposure time of anticancer drugs in tumors can be accomplished by decreasing tumor tissue blood flow (tBF) after anticancer drug administration. The present study demonstrated that temocapril hydrochloride, an angiotensin converting enzyme inhibitor, decreases tumor tBF markedly in LY80 tumor, a subline of Yoshida sarcoma in the rat, without affecting the blood flow in liver, kidney, bone marrow, and brain. In tumor areas with flow of above 20 ml/min/100 g, the tBF decreased by approximately 50% due to temocapril. In tumor areas with tBF of about 20 ml/min/100 g, it became less than 3 ml/min/100 g with temocapril and did not recover during the 2 h experiment. These findings were obtained not only in large tumors, but also in microfoci growing within a transparent chamber. Furthermore, even when temocapril was administered under the condition of increased tumor tBF by administering angiotensin II, tumor tBF decreased immediately. Using this technique, it should be possible to trap anticancer drugs selectively in tumor tissue for an extended period of time.     

Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors

Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration‐dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.     

Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient

Human breast tumors often exist in an acidic and hypoxic microenvironment, which can promote resistance to radiation and chemotherapies. A tumor-selective pH gradient arises in these tumors which favors uptake and retention of drugs like camptothecin that are weak acids. We evaluated the effect of alkyl substitutions at the 7 position in seven CPTs with varying groups at the 10 position on modulation by acidic extracellular pH in three human breast cancer cell lines. Growth inhibition was assessed by propidium iodide staining of nucleic acids in human breast cancer cells cultured at either extracellular pH 6.8 or 7.4 that were (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc). Over 10-fold pH modulation was observed in 7-halomethyl analogs of methylenedioxy-CPT and in 7-alkyl analogs of 10-amino-CPT. Of 39 analogs tested, the overall pattern of activity across breast tumor cell lines was similar with some notable exceptions. For example, 7-propyl-10-amino-CPT was modulated 16- to 20-fold by acidic extracellular pH in the MCF-7 cell lines, but only 6-fold in MDA-MB-231 cells. One mechanism that can contribute to pH modulation is enhanced cellular drug uptake and retention. In MCF-7/wt cells, uptake of 10-amino-CPT increased 4-fold, while retention increased over 10-fold at acidic extracellular pH. In addition, gene expression analysis of MCF-7/wt cells indicated that expression of a number of genes changed under acidic culture conditions, including down-regulation of the CPT efflux protein pump breast cancer resistance protein (BCRP). Interestingly, expression of topoisomerase I, the molecular target of CPT, was not affected by acidic growth conditions. These results highlight the importance of maintaining key features of tumor physiology in cell culture models used to study cancer biology and to discover and develop new anticancer drugs. While several substitutions at the 7 and 10 positions enhance potency, 7-halomethyl and 10-amino CPT analogs show selective activity at the acidic pH common to the microenvironment of most solid tumors. The work is dedicated to the memory of Dr. Monroe E. Wall, who inspired this research team and many other investigators committed to creating useful anticancer drugs from natural products.     

RhoA亚家族与胃癌细胞恶性表型的关系

目的:研究RhoA亚家族成员RhoA、RhoB和RhoC对胃癌细胞恶性表型的影响。方法:系用脂质体介导法分别将编码正显性RhoA突变体(V14RhoA)与野生型RhoB(wt-RhoB)和RhoC(wt-RhoC)的真核表达载体转染入胃癌SGC7901细胞中,筛选出稳定抗性克隆,并检测转染细胞的生物学行为的变化。结果:RhoA活性增强可促进胃癌细胞的增殖,而降低对化疗药物的敏感性;上调RhoB表达抑制胃癌细胞的增殖,增强对化疗药物的敏感性;上调表达RhoC则对胃癌细胞的增殖及对化疗药物的敏感性无明显的影响,但可明显促进胃癌细胞的迁移。结论:RhoA亚家族分子参与了胃癌生长、耐药及转移等多个方面,其家族中不同分子作用不同。     

Differential influence of pentoxifylline on murine colon adenocarcinoma- and melanoma-derived metastatic tumor development in lungs

Pentoxifylline (PTX), a methylxanthine derivative, is commonly and in most cases chronically used in patients suffering from peripheral vascular diseases. It increases erythrocyte flexibility, reduces blood viscosity and improves microcirculatory flow. Moreover, PTX has been found to enhance anticancer activity of some chemotherapeutic agents and ionizing irradiation. On the other hand, PTX has been recently shown to inhibit anticancer response and promote murine tumor growth in liver. In this study we show that PTX facilitates development of murine colon adenocarcinoma- but not melanoma-derived tumors also in lungs. It could suggest that tumor-promoting PTX activity is tissue-independent, although, it might depend on the cancer cell line.     

Enhancement of antitumor effect by intratumoral administration of bax gene in combination with anticancer drugs in gastric cancer

Proapototic gene is an important target to enhance the chemotherapeutic effect in cancer cells. Based on in vitro study showing that the introduction of bax gene enhanced the sensitivity to anticancer drugs, we examined whether the intratumoral administration of bax gene could enhance the anti-tumor effect in combination with anticancer drugs in gastric cancer. The human gastric cancer cell line, MKN45 was transplanted into nude mice, and the intratumoral administration of bax gene was performed using the bax cDNA plasmid complexed with a cationic lipopolyamine. The enhancement of antitumor effect was examined in the combination with 5-fluorouracil (5-FU) and cisplatin (CDDP). The anticancer drugs were administered intraperitoneally with one third of LD50 four times at 4-day intervals, and the antitumor effect was assessed by the NCI protocol. The expression of bax gene was analyzed by RT-PCR and the apoptotic cell death was assessed by TUNEL method. The intratumoral administration of bax gene alone showed slight anti-tumor effect as compared to that of control tumor injected with vector alone. The antitumor effect of 5-FU and CDDP was significantly enhanced in the combination with intra-tumoral administration of bax gene as compared to that of CDDP and 5-FU alone (p<0.05, Student's t-test). The enhancement of antitumor effect was associated with the constitutive overexpression of bax gene and with the induction of apoptosis in the tumor treated with anticancer drug and bax gene. These results indicate that the combination therapy of intratumoral administration of bax gene complexed with a cationic lipopolyamine and anticancer drugs may provide us a new strategy for cancer chemotherapy to enhance its therapeutic efficacy in gastric cancer as termed with gene-chemotherapy.     

Persistent vascular normalization as an alternative goal of anti-angiogenic cancer therapy

Angiogenesis is recognized as one of the principal hallmarks of cancers. Cancers contain newly formed immature vessels devoid of firm coverage by pericytes. Several drugs targeting vascular endothelial growth factor signals are now in clinical use for anti-angiogenic cancer treatment. Those drugs transiently normalize tumor vessels and ultimately provoke vascular regression. This regression causes tumor hypoxia, which could trigger certain cancer cells to become more invasive and metastatic. Normalized vessels do not induce tumor hypoxia, and may protect from cancer cell intravasation and enhance anticancer treatment with chemotherapeutic agents, radiation, or immune therapy. Thus, persistent vascular normalization could be an alternative goal of anti-angiogenic cancer treatment.     

表达Tie2的单核细胞在肿瘤研究中的进展

表达Tie2的单核细胞(TEM)仅存在于外周血及肿瘤组织中,在肿瘤血管生成中发挥重要作用.TEM能够被血管生成素2(Ang2)及缺氧化学信号募集进入肿瘤组织,分化成表达Tie2的巨噬细胞,通过旁分泌作用参与肿瘤血管生成.肝癌、结肠癌、乳腺癌、恶性胶质瘤等肿瘤中检测到TEM水平升高,这对于肿瘤的诊断及预后判断有一定的提示作用.近年研究发现,TEM可用于抗肿瘤药物的靶向递送,能有效抑制肿瘤的生长和转移,同时TEM也是抗肿瘤治疗的潜在靶点.然而TEM在肿瘤微血管密度、临床分级及预后判断中的作用并不明确,目前针对TEM具体功能的探究引起了学者的广泛关注.