N6-甲基腺苷修饰及其在胃癌化疗耐药作用中的研究进展

胃癌是我国最常见的消化系统恶性肿瘤，其化疗耐药问题日趋严重，导致治疗有效率下降。N6-甲基腺苷（m6A）修饰作为真核生物中最丰富的RNA内部修饰，影响RNA的加工、调节mRNA翻译效率和稳定性，在胃癌中调控肿瘤基因和蛋白的表达水平，导致肿瘤细胞对化疗产生抵抗。m6A修饰在胃癌化疗耐药中的双重作用可为平衡机体获得耐药过程提供思路。全文对m6A修饰及其在胃癌化疗耐药中的功能和作用机制的研究进展等进行综述，以期为临床防治m6A修饰失衡引起的胃癌化疗耐药提供理论参考及依据。     

恶性肿瘤pH依赖性生理性耐药及其对策

目前绝大多数的肿瘤耐药机制研究均集中于肿瘤细胞基因和蛋白水平,而对肿瘤组织微环境的关注则相对较少.恶性实体瘤实际上是一个类似于器官的异质性实体结构,肿瘤组织微环境中的理化因子,例如肿瘤局部pH值、血流、压力和氧供等,均会对药物的疗效产生重要的影响.上述现象被定义为“生理性耐药”,其不同于信号通路或蛋白表达改变所引起的耐药.本文将重点介绍肿瘤组织局部pH值变化引起的耐药,即pH依赖性生理性耐药(pH-induced physiological drug resistance,PIPDR)的产生及其临床意义.     

肿瘤相关成纤维细胞的代谢重编程与肿瘤进展的关系

肿瘤的生长并不完全由肿瘤细胞本身决定,肿瘤相关成纤维细胞(CAF)是肿瘤微环境的主要组成部分,在肿瘤的代谢、生长、转移、免疫逃逸和化疗耐药等方面具有重要作用。CAF的代谢重编程使其更倾向于有氧糖酵解,被称为"温伯格效应"。目前认为,CAF的代谢重编程调控机制可能与致癌基因c-myc、缺氧诱导因子1α和腺苷一磷酸(AMP)活化的蛋白激酶有关。代谢重编程的CAF可通过多种途径促进肿瘤的生长、发展:肿瘤微环境中的CAF可以通过分泌大量的细胞因子、趋化因子和促血管生成因子间接或直接调节肿瘤免疫;通过调节肿瘤间质液压、酸化肿瘤微环境,以及分泌可溶性因子促进肿瘤耐药;肿瘤组织中的CAF可募集抑制性免疫细胞,在肿瘤局部形成抑制性免疫微环境,促进上皮-间充质转化,激活肿瘤细胞增殖的信号通路从而促进肿瘤生长、耐药,形成恶性循环。阻断肿瘤、CAF和免疫微环境间的相互作用,可能成为未来肿瘤治疗的靶点。     

脑肿瘤微环境影响胶质母细胞瘤侵袭行为的研究进展

多形性胶质母细胞瘤(glioblastoma multiforme,GBM)是最常见的神经系统恶性肿瘤,目前尚缺乏十分有效的治疗策略。造成GBM死亡率居高不下的主要原因在于其在脑内发生广泛的浸润。肿瘤微环境是一个由肿瘤细胞、细胞外基质、基质细胞、细胞因子、免疫细胞等共同构成的肿瘤局部的病理环境,具有组织缺氧、酸中毒、间质高压等特点。GBM的侵袭行为与脑肿瘤微环境紧密相关。本文就肿瘤微环境中各因素影响GBM侵袭行为的研究进展进行综述。     

肿瘤化疗增敏剂研究进展

化疗增敏剂通过逆转肿瘤组织耐药而提高化疗疗效。其作用机制包括：抑制药物泵功能；针对谷胱甘肽代谢相关酶、拓扑异构酶Ⅱ、DNA修复相关酶、蛋白激酶C等靶点逆转耐药；促凋亡；干扰肿瘤细胞与组织微环境之间耐药信号转导等。现按其作用机制，分类介绍化疗增敏剂的研发现状。     

逆转录-多聚酶链式反应方法检测临床肝癌组织的多药耐药基因表达

化疗是治疗肿瘤的有效手段之一。肿瘤细胞耐药是导致化疗失败的主要原因，有关资料统计，９０％以上肿瘤患者死因或多或少都与耐药有关〔１〕。因此，研究肿瘤耐药起因、检测病人是否出现耐药，借以指导临床化疗，提高患者治愈率和生存率，这是当前肿瘤治疗迫切需要解决的...     

乳腺癌肿瘤微环境中间质细胞介导的化疗耐药性研究进展

乳腺癌是一种具有异质性的全身性疾病,其微环境主要由肿瘤细胞及多种非肿瘤细胞组成。其中间充质干细胞在肿瘤的发生发展中发挥着重要作用。间充质干细胞可直接通过缝隙连接、膜受体和微管或间接通过可溶性分子与肿瘤细胞及其微环境相互作用。肿瘤相关成纤维细胞来源于癌旁成纤维细胞或间充质干细胞,在肿瘤耐药过程中发挥重要作用。在乳腺癌中,肿瘤干细胞与其所处微环境处于动态平衡状态,其表型受细胞因子的密切调控。间质细胞通过与乳腺癌细胞的相互作用,进而对其生物学特性产生重要影响。另外,间质细胞可改变肿瘤细胞对化疗药物的敏感性,进而使其产生耐药。因此,解决肿瘤间质细胞介导的化疗耐药是成功治疗中晚期乳癌的关键。本文主要阐述了间质细胞在乳腺癌微环境中介导化疗耐药的研究进展。     

细胞粘附与耐药在血液系统肿瘤中的研究

细胞粘附介导的耐药(CAM-DR)使肿瘤细胞初始暴露于细胞毒药物时在肿瘤微环境中受到庇护，最终导致肿瘤细胞残留和经典耐药发生。造血微环境中的细胞外基质、骨髓基质细胞和细胞因子均参与血液系统肿瘤CAM-DR的发生，对疾病复发和耐药起重要作用。     

肿瘤化疗增敏剂研究进展

化疗增敏剂通过逆转肿瘤组织耐药而提高化疗疗效。其作用机制包括：抑制药物泵功能；针对谷胱甘肽代谢相关酶、拓扑异构酶Ⅱ、DNA修复相关酶、蛋白激酶C等靶点逆转耐药；促凋亡；干扰肿瘤细胞与组织微环境之间耐药信号转导等。现按其作用机制,分类介绍化疗增敏剂的研发现状。     

缺氧诱导因子-1α在恶性肿瘤中的研究进展

肿瘤的发生、发展与细胞的过度增殖和凋亡的减少有关，肿瘤细胞无限制的增殖是其主要的特征，而细胞增殖需要大量耗氧，研究证实缺氧是实质性肿瘤物理微环境的基本特征之一。肿瘤的缺氧不仅是发生恶性转化的始动因素，还可以诱导肿瘤细胞对放疗及化疗的耐受性，促进肿瘤的浸润和转移等恶性生物学行为的发生，缺氧导致的一系列基因和蛋白的表达正是这些现象发生的根本原因。缺氧诱导因子-1α（hypoxia inducible factor 1 alpha，HIF-1α）在肿瘤的血管生成和能量代谢中起重要的调控作用。     

层黏连蛋白受体参与缺氧诱导胃癌多药耐药的机制研究

目的:研究缺氧对胃癌细胞对于化疗药物敏感性的影响以及层黏连蛋白受体在缺氧诱导的胃癌MDR中的作用和分子机制。方法:MTT比色法、Annexin V/PI染色法和阿霉素的蓄积和潴留实验检测胃癌细胞在缺氧和常氧状态下对化疗药物敏感性的差异;Western blot和半定量RT-PCR检测缺氧条件下胃癌细胞中67Kda层黏连蛋白受体(67Kda laminin receptor,67LR)的表达;Western blot、半定量RT-PCR方法检测缺氧条件下胃癌细胞系SGC7901中67LR的表达和活性;利用siRNA干涉67LR的表达,MTT比色法、AnnexinV/PI染色法检测缺氧条件下调下胃癌细胞系67LR的表达对化疗药物敏感性的影响。结果:缺氧能够显著降低胃癌细胞对化疗药物的敏感性,以及化疗药物诱导的凋亡和药物在细胞内的潴留和蓄积;缺氧能够显著上调67LR的表达和转录活性;67LR siRNA能够抑制LR的表达;抑制67LR的表达能够显著逆转缺氧诱导的胃癌的MDR表型。结论:缺氧能够增加胃癌细胞对于化疗药物的抵抗,通过上调67LR表达,加剧了缺氧诱导的胃癌多药耐药表型,抑制67LR的表达能够逆转缺氧诱导的胃癌多药耐药的发生。     

层黏连蛋白受体参与缺氧诱导胃癌多药耐药的机制研究

目的：研究缺氧对胃癌细胞对于化疗药物敏感性的影响以及层黏连蛋白受体在缺氧诱导的胃癌MDR中的作用和分子机制。方法：MTT比色法、Annexin V/PI染色法和阿霉素的蓄积和潴留实验检测胃癌细胞在缺氧和常氧状态下对化疗药物敏感性的差异;Western blot和半定量RT-PCR检测缺氧条件下胃癌细胞中67Kda层黏连蛋白受体（67Kda laminin receptor,67LR）的表达;Western blot、半定量RT-PCR方法检测缺氧条件下胃癌细胞系SGC7901中67LR的表达和活性;利用siRNA干涉67LR的表达,MTT比色法、AnnexinV/PI染色法检测缺氧条件下调下胃癌细胞系67LR的表达对化疗药物敏感性的影响。结果：缺氧能够显著降低胃癌细胞对化疗药物的敏感性,以及化疗药物诱导的凋亡和药物在细胞内的潴留和蓄积;缺氧能够显著上调67LR的表达和转录活性;67LR siRNA能够抑制LR的表达;抑制67LR的表达能够显著逆转缺氧诱导的胃癌的MDR表型。结论：缺氧能够增加胃癌细胞对于化疗药物的抵抗,通过上调67LR表达,加剧了缺氧诱导的胃癌多药耐药表型,抑制67LR的表达能够逆转缺氧诱导的胃癌多药耐药的发生。     

胰腺癌抑制性免疫微环境促进肿瘤细胞化疗耐药的研究进展

胰腺癌微环境中存在多种免疫抑制细胞,表达不同的细胞因子抑制机体的免疫杀伤功能,在肿瘤发展中发挥重要的作用。这些细胞还能影响化疗药物杀伤肿瘤细胞的功能,促进肿瘤细胞耐药。吉西他滨、白蛋白结合型紫杉醇等胰腺癌一线化疗药物不仅可直接抑制肿瘤细胞增殖,还可作用于免疫细胞间接增强抗肿瘤作用。相反,化疗药物也能增强免疫抑制细胞功能,诱导耐药,促进肿瘤进展。本文就胰腺癌微环境的免疫抑制状态,及其与化疗药物之间作用机制做一综述,旨在从肿瘤免疫微环境的角度优化现有的化疗策略。      

Chemosensitization of cancer in vitro and in vivo by nitric oxide signaling.

PURPOSE: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro. Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo. EXPERIMENTAL DESIGN: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. RESULTS: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxia-induced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. CONCLUSION: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.     

Molecular mechanisms of chemoresistance in gastric cancer

Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.     

Dynamic cellular biomechanics in responses to chemotherapeutic drug in hypoxia probed by atomic force spectroscopy

The changes in cellular structure play an important role in cancer cell development, progression, and metastasis. By exploiting single-cell, force spectroscopy methods, we probed biophysical and biomechanical kinetics (stiffness, morphology, roughness, adhesion) of brain, breast, prostate, and pancreatic cancer cells with standard chemotherapeutic drugs in normoxia and hypoxia over 12–24 hours. After exposure to the drugs, we found that brain, breast, and pancreatic cancer cells became approximately 55–75% less stiff, while prostate cancer cells became more stiff, due to either drug-induced disruption or reinforcement of cytoskeletal structure. However, the rate of the stiffness change decreased up to 2-folds in hypoxia, suggesting a correlation between cellular stiffness and drug resistance of cancer cells in hypoxic tumor microenvironment. Also, we observed significant changes in the cell body height, surface roughness, and cytoadhesion of cancer cells after exposure to drugs, which followed the trend of stiffness. Our results show that a degree of chemotherapeutic drug effects on biomechanical and biophysical properties of cancer cells is distinguishable in normoxia and hypoxia, which are correlated with alteration of cytoskeletal structure and integrity during drug-induced apoptotic process.     

低氧肿瘤微环境和低氧诱导因子对CSCs、EMT及CTCs的重要意义

低氧是所有实体肿瘤的普遍特性,是肿瘤微环境的一个重要标记。越来越多的证据表明肿瘤细胞的行为特征很大程度上受微环境的影响。肿瘤细胞通过调控低氧诱导因子（HIFs）适应低氧微环境。微环境低氧促进了肿瘤干细胞（CSCs）和循环肿瘤细胞（CTCs）的生成,加快了细胞上皮表型向间质表型的转化（EMT）,并增加了肿瘤浸润、转移和耐药的机率。改善低氧肿瘤微环境能够阻碍肿瘤的发生和发展。     

Role of cancer-associated fibroblasts in the resistance to antitumor therapy,and their potential therapeutic mechanisms in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described.