糖酵解与肿瘤

肿瘤细胞主要通过糖酵解获取能量促进其生长,这与线粒体DNA变异和抑癌基因突变有关。抑制糖酵解具有抑制增殖和杀伤肿瘤细胞的作用。糖酵解限速酶和低氧诱导因子有望成为治疗肿瘤的新靶点。     

肿瘤细胞的异常糖代谢

肿瘤细胞糖代谢异常与多种机制有关,如缺氧诱导因子（HIF）的参与可激活糖酵解相关酶类,有利于肿瘤细胞采取糖酵解方式获能;线粒体功能低下或数量减少可一定程度抑制葡萄糖氧化磷酸化途径;某些癌基因的激活及抑癌基因的失活也参与调节线粒体氧化呼吸链及糖酵解相关酶类,从而影响糖代谢过程;肿瘤细胞氧化磷酸化的相关酶类合成受到抑制等。此外,糖代谢异常对肿瘤细胞的生长、侵袭和转移具有重要作用。     

丙酮酸脱氢酶与肿瘤

丙酮酸脱氢酶是丙酮酸生成乙酰辅酶A的关键酶,而乙酰辅酶A是葡萄糖进入三羧酸循环有氧氧化的首要原料。丙酮酸脱氢酶激酶可以抑制丙酮酸脱氢酶的活性。肿瘤细胞的总体丙酮酸脱氢酶激酶表达增加,造成丙酮酸脱氢酶活性降低,导致肿瘤细胞主要通过糖酵解的方式获取能量。恶性肿瘤糖酵解活跃能促进细胞增殖和抑制细胞凋亡,而形成肿瘤细胞糖酵解的微环境可保护肿瘤细胞逃避宿主免疫杀伤并减轻化疗药物损伤,还有利于肿瘤细胞的侵袭和转移。因此,丙酮酸脱氢酶在肿瘤的发生发展过程中起作用。事实上胚胎干细胞以及成体干细胞也主要是以糖酵解的方式获取能量。由此推断,丙酮酸脱氢酶的活性可能与肿瘤细胞的干性相关。     

肿瘤细胞的糖酵解能量代谢机制

肿瘤细胞与正常分化细胞对比有着不同的能量代谢表型, 其多通过糖酵解途径消耗更多的葡萄糖, 并产生大量的乳酸, 却很少利用氧化磷酸化(OXPHOS)进行产能。但肿瘤细胞高糖酵解能量代谢表型的具体分子机制目前尚不完全明确。肿瘤细胞高糖酵解活性可能涉及到糖酵解酶和葡萄糖转运蛋白过表达、OXPHOS酶系和转运蛋白的低表达、线粒体含量减低及DNA对氧化应激的高敏性等机制。然而, 肿瘤细胞间遗传、生化和形态学上存在异质性, 其升高的糖酵解活性均有自己的不同机制。本文对肿瘤细胞高糖酵解活性的基因和生化调节机制进行具体分析, 并讨论肿瘤细胞降低的线粒体代谢和OXPHOS功能的机制。提示肿瘤细胞能量代谢的差异可作为高糖酵解肿瘤细胞的一个治疗靶向。      

肿瘤细胞糖酵解途径的抗肿瘤研究

肿瘤细胞的葡萄糖代谢主要呈现出瓦博格效应(Warburg effect).近年来,越来越多的实验证实基于肿瘤细胞有氧糖酵解途径的治疗可通过抑制多种分子、基因和信号途径限制能量供应,抑制肿瘤细胞增殖.这为肿瘤的靶向治疗提供了契机,具有巨大的潜在优势和广阔的临床应用前景.     

T细胞糖代谢重编程与抗肿瘤免疫治疗的研究进展

肿瘤细胞主要通过有氧糖酵解获取能量。然而,肿瘤微环境（TME）中的成熟T细胞也会发生代谢重编程,通过有氧糖酵解获取能量,维持T细胞增殖和活性。快速增殖的肿瘤细胞可与TME中的其他细胞竞争营养物质,导致T细胞能量供给的相对缺乏和糖酵解水平的低下,从而影响T细胞抗肿瘤作用的发挥。T细胞葡萄糖缺乏可诱导PD-1分子的过表达,进而介导免疫耐受的发生。此外,PD-L1/PD-1的结合可激活T细胞并抑制糖酵解反应,降低T细胞的杀伤活性。c-Myc和缺氧诱导因子1α等分子对T细胞代谢具有重要调控作用。恢复TME中的T细胞代谢和抗肿瘤效应,具有重要的转化医学价值。本文综述了近年来肿瘤细胞与T细胞糖代谢重编程相互作用方面的研究进展,以及改善肿瘤免疫治疗的潜在策略。     

恶性肿瘤的代谢与免疫逃逸

恶性肿瘤的发生发展意味着肿瘤细胞适应了不利的环境。肿瘤细胞代谢往往降低线粒体活性和氧化磷酸化过程,在很大程度上依赖有氧糖酵解产生能量。这特定的新陈代谢造成肿瘤微环境的变化,帮助肿瘤细胞得以生存、转移及免疫逃逸,而免疫逃逸包括抑制和阻断肿瘤的免疫反应。这一效应通过许多机制实现,包括肿瘤代谢过程及代谢产物对免疫系统直接和间接的抑制和阻断作用。     

Akt及其在肿瘤细胞糖酵解中的作用

Akt通过对葡萄糖转运子、己糖激酶和柠檬酸裂解酶等因子的作用,达到增强肿瘤细胞糖酵解的效应.Akt在肿瘤细胞中的异常升高对肿瘤细胞糖代谢产生影响,继而对肿瘤细胞的生存能力、增殖能力、抗凋亡等有一定作用.抑制Akt磷酸化水平可抑制癌细胞生长.因此,Akt可作为肿瘤临床治疗的新靶点.     

己糖激酶Ⅱ与肿瘤增殖及靶向治疗

肿瘤细胞所需能量主要来自有氧糖酵解途径,即Warburg效应,该生化过程同时为肿瘤细胞提供生长所需的大量前体物质.已糖激酶Ⅱ(HK-Ⅱ)为糖酵解的限速酶,在肿瘤组织中高表达,与肿瘤的能量代谢密切相关.近年来研究表明肿瘤细胞中的HK-Ⅱ不仅介导Warburg效应,还能抑制肿瘤细胞凋亡、调节自噬而发挥促进肿瘤增殖的作用.已在多种肿瘤细胞中证实,阻断HK-Ⅱ基因表达及应用HK-Ⅱ的小分子抑制剂均可起到杀伤肿瘤的作用,以HK-Ⅱ为靶点的抑制剂有可能成为新一代靶向药物.     

有氧糖酵解促进肿瘤转移及干性的研究进展

癌症已成为全球第二大死亡原因,是危害严重的全球健康问题。虽然医学发展迅速,治疗方法也在不断改进,可是由于肿瘤复发和远端转移的存在,目前肿瘤患者仍然预后不良,生存率无法提高。近期肿瘤细胞中的“代谢重编程”给我们提供了新的思路,肿瘤细胞中从氧化磷酸化到糖酵解的代谢转换可以影响肿瘤细胞干性,参与调节肿瘤的侵袭与远端转移。本文总结了近年来关于肿瘤细胞有氧糖酵解的相关研究,就肿瘤细胞中的糖代谢重编程、糖酵解对肿瘤细胞转移及干性的影响,以及潜在机制几方面进行综述,探讨靶向糖酵解联合治疗的可行性,希望有助于肿瘤细胞糖代谢后续的研究,为肿瘤治疗提供新的策略。     

The role of FLT3 in haematopoietic malignancies

Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in approximately 25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.     

线粒体DNA变异与肿瘤的相关性研究进展

肿瘤的发生发展是一个较为复杂的生物学过程,其中线粒体在肿瘤细胞代谢过程中扮演重要角色。线粒体DNA（mitochondrial DNA,mtDNA）变异包括点突变、缺失、插入以及拷贝数变异等,这些变异可能参与肿瘤细胞的增殖、生长、侵袭和转移。本文就mtDNA突变、拷贝数改变、mtDNA与核基因（nuclear DNA,nDNA）的比值,以及mtDNA变异与肿瘤发生发展的相关性研究及临床进展进行综述,旨在为深入认识mtDNA变异与肿瘤发生发展的关系并为临床治疗提供更多的参考依据。      

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

Tumor‐derived cell lines are indispensable tools for understanding the contribution of activated signaling pathways to the cancer phenotype and for the design and testing of targeted signal therapies. In our study, we characterize 10 colorectal carcinoma cell lines for the presence of mutations in the wnt, Ras/MAPK, PI3K and p53 pathways. The mutational spectrum found in this panel of cell lines is similar to that detected in primary CRC, albeit with higher frequency of mutation in the β‐catenin and B‐Raf genes. We have monitored activation of the wnt and Ras/MAPK pathways in these cells and analyzed their sensitivity to selective signaling inhibitors. Using β‐catenin subcellular distribution as a marker, we show that cells harboring APC mutations have low‐level activated wnt signaling, which can be blocked by the extracellular wnt inhibitor DKK‐1, suggesting autocrine activation of this pathway; proliferation of these cells is also blocked by DKK‐1. In contrast, cells with β‐catenin mutations are unresponsive to extracellular wnt inhibition. Constitutive phosphorylation of MAPK is present in the majority of the cell lines and correlates with B‐Raf but not K‐Ras mutations; correspondingly, the proliferation of cells harboring mutations in B‐Raf, but not K‐Ras, is exquisitely sensitive inhibition of the MAPK pathway. We find no correlation between PI3K mutation or loss of PTEN expression and increased sensitivity to PI3K inhibitors. Our study discloses clear‐cut differences in responsiveness to signaling inhibitors between individual mutations within an activated signaling pathway and suggests likely targets for signal‐directed therapy of colorectal carcinomas. © 2009 UICC     

Quinidine impairs proliferation of neurofibromatosis type 2-deficient human malignant mesothelioma cells

BACKGROUND: Human malignant mesotheliomas (HMMs) are aggressive tumors that arise from the mesothelium. They respond poorly to conventional tumor treatment and outcome is often fatal. Inactivating mutations of the neurofibromatosis type 2 (NF2) tumor suppressor gene merlin have been described in nearly 60% of primary malignant mesothelioma and in approximately 20% of the mesothelioma cell lines. Studies regarding human NF2 schwannoma cells revealed a higher proliferation and a larger noninactivating K(+) outward current compared with controls. The enhanced proliferation of merlin-deficient NF2 schwannoma cells could be reduced in the presence of quinidine, a K(+) channel blocker, whereas the proliferation of normal Schwann cells is not affected. The current study was undertaken to evaluate the effect of quinidine on the proliferation of HMM cell lines in relation to their NF2 status. METHODS: Proliferation analyses using bromodeoxyuridine incorporation was performed by immunocytochemical staining and fluorescence assisted cell sorting. The patch-clamp technique was applied for electrophysiologic characterization of the HMM cell lines. The cytochrome P450 2D6 locus, known to be mutated at high frequencies in NF2 patients and to be specifically inhibited by quinidine, was screened for mutations by cycle sequencing. RESULTS: Quinidine selectively reduces the proliferation of merlin-deficient HMM cell lines by causing a G(0)/G(1) arrest, whereas the proliferation rates of merlin-expressing HMM cell lines remain unchanged. The effect of quinidine on the proliferation of HMM cell lines appears to be correlated with the NF2 gene status but not with the K(+) outward current. No relation to cytochrome P450 2D6 mutations was detected. CONCLUSIONS: Quinidine or quinidine analogs are of potential therapeutic interest for the subset of merlin-deficient mesothelioma tumors.     

Anti-proliferative effects of green tea polyphenol EGCG on Ha-Ras-induced transformation of intestinal epithelial cells

Oncogenic Ras mutations are frequently observed in colorectal cancer and participate in neoplastic transformation of intestinal epithelial cells. Accumulating evidence demonstrates the chemopreventive properties of green tea on colon carcinogenesis. Here we investigated the major green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), to inhibit proliferation of intestinal epithelial cells (RIE-1) transfected with an inducible Ha-Ras(Val12) cDNA. EGCG inhibited cell proliferation induced by oncogenic Ras and blocked cell cycle transition at G1 phase via inhibition of cyclin D1 expression. The EGCG IC(50) was 42microM in transformed cells and 81microM in non-transformed cells. EGCG also promoted E-cadherin expression, which is downregulated by Ras transformation. This study demonstrates the potential of the natural compound EGCG as an effective adjuvant therapy for colon tumors bearing Ras mutations.     

急性淋巴细胞白血病基因突变的研究进展

急性淋巴细胞白血病（acute lymphoblastic leukemia，ALL）是淋巴细胞早期发育异常，发生恶性增殖所致的疾病，其特点是造血细胞的异常增殖与病理性分化。通过了解ALL患者的分子生物学与细胞遗传学信息，有助于预测患者的预后。基因突变与发病密切相关，是一项独立的预后因素。近年来，随着测序技术的发展，越来越多与ALL发生与发展相关的突变基因被发现，可通过对高危患者早期干预，以改善其预后。某些基因突变还可成为治疗该病的潜在靶点，为靶向药物的研究与应用提供了可能。本文对近年来在ALL中常见基因突变的研究进展进行综述。      

Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells

Activation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in the pathogenesis of a variety of cancers. Recently, mutations in the gene encoding the p110alpha catalytic subunit of PI3K (PIK3CA) have been identified in several human cancers. The mutations primarily result in single amino acid substitutions, with >85% of the mutations in either exon 9 or 20. Multiple studies have shown that these mutations are observed in 18% to 40% of breast cancers. However, the phenotypic effects of these PIK3CA mutations have not been examined in breast epithelial cells. Herein, we examine the activity of the two most common variants, E545K and H1047R, in the MCF-10A immortalized breast epithelial cell line. Both variants display higher PI3K activity than wild-type p110alpha yet remain sensitive to pharmacologic PI3K inhibition. In addition, expression of p110alpha mutants in mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells, including anchorage-independent proliferation in soft agar, growth factor-independent proliferation, and protection from anoikis. Expression of these mutant p110alpha isoforms also confers increased resistance to paclitaxel and induces abnormal mammary acinar morphogenesis in three-dimensional basement membrane cultures. Together, these data support the notion that the cancer-associated mutations in PIK3CA may significantly contribute to breast cancer pathogenesis and represent attractive targets for therapeutic inhibition.