肿瘤坏死因子相关凋亡诱导配体耐药机制研究进展

肿瘤化疗药物耐药是肿瘤临床治疗面临的主要障碍。肿瘤坏死因子相关凋亡诱导配体(TRAIL)是肿瘤坏死因子(TNF)家族中新发现的一个配体成员,通过与肿瘤细胞死亡受体DR4或DR5相互作用,从而启动细胞凋亡,被认为对肿瘤细胞具有选择性杀伤作用,因而在肿瘤治疗上具有较好的应用前景。然而,多种肿瘤细胞可对TRAIL产生耐药,使得TRAIL在临床应用受到很大限制。对近年来报道的TRAIL耐药的相关分子靶点和信号通路进行总结,主要包括异常的蛋白质合成、内质网应激途径、泛素调节死亡受体表达、热休克蛋白、细胞自我吞噬等相关信号,为肿瘤TRAIL耐药患者提供新的治疗靶点和思路。     

放射对肿瘤细胞增殖和促血管生成因子表达的影响

放射治疗是肿瘤治疗的重要手段 ,但放疗后临床完全缓解只是表示肿瘤细胞降到一定数量 (1× 10 9个 )以下 ,并不等于治愈。根治量放疗后肿瘤的复发及转移一直是肿瘤放射治疗中难以解决的问题 ,对肿瘤首程放疗后复发或转移者的治疗效果往往很差。放射对肿瘤细胞增殖和转移的生物学行为影响的研究 ,对肿瘤治疗有重要的指导意义。1　放射与肿瘤细胞的增殖1 .1　放射治疗中肿瘤细胞的加速再增殖在放射治疗疗程中 ,肿瘤细胞的增殖速率不一 ,在某一些时间里会出现细胞的加速再增殖。肿瘤细胞加速再增殖的确切原因和机理 ,目前尚未完全明了 ,可能与…     

金丝桃素介导的光动力学疗法在肿瘤治疗中的应用研究

主要介绍了金丝桃素的理化性质、光敏活性和药理活性,详细阐述了金丝桃素作为一种新型光敏剂在肿瘤治疗的应用,重点介绍了金丝桃素抑制肿瘤细胞生长的各种抗肿瘤机制,为肿瘤的临床治疗提供理论依据。     

肿瘤转移相关基因及因子的研究进展

肿瘤转移是恶性肿瘤治疗失败和患者死亡的主要原因。目前已知肿瘤的侵袭、转移包括从原发部位浸润性生长、穿透细胞外基质、进入血管、淋巴管或体腔中游走、与靶器官黏附后向间质侵袭以及增殖形成转移灶等几个阶段，这是一个多步骤、多阶段、多基因的复杂过程。近年来，肿瘤分子生物学的研究重点逐渐转入分离和克隆肿瘤转移基因（MG）与肿瘤转移抑制基因（MSG），并对这些基因的调控因子和转移过程中的作用机制进行深入研究，期望在基因水平揭示肿瘤转移的本质，为改进肿瘤的诊断方法和治疗手段提供依据。在细胞基因组中，具有促进肿瘤细胞浸润或转移潜能的基因称为肿瘤转移基因，这类基因亦称为肿瘤转移促进基因（metastasis—enhancing gene）。MSG能抑制肿瘤细胞的转移，但不影响原发肿瘤的生长。     

黄连素抗癌特性的研究进展

黄连素是一种具有丰富生物学活性的植物。近半个世纪以来,发现黄连素在体内外均具有一定程度的抗癌功效,能抑制肿瘤细胞的侵袭性,降低自发的和外界刺激诱导的肿瘤细胞增殖,干预耐药蛋白的表达,增加肿瘤细胞对传统放化疗的敏感性,影响多种基因的表达,从而实现对肿瘤增殖和转移的抑制。本文就介绍黄连素的抗癌功效及部分机制作一综述。     

热环境对乳腺肿瘤生长的影响

创新性地探讨了持续热环境对乳腺肿瘤生长的影响。采用BALB／c4T1荷瘤小鼠建立乳腺癌模型,将自行设计的加热片置于接种在BALB／c小鼠背部皮下的肿瘤表面,在肿瘤周围局部造成温热环境,使肿瘤底部温度达到38℃,每天持续加热12h,分别加热3、7、14和21d。实验结果表明持续热环境使肿瘤生长速率明显降低。组织病理学研究结果表明当加热21d,肿瘤细胞大量坏死,持续的热疗对肿瘤细胞有明显的杀伤效应。同时,对加热后肿瘤组织内乳酸和ATP代谢产物进行测定,结果显示加热组小鼠肿瘤内部乳酸和ATP浓度低于对照组。持续的热环境,作为一种外界的能量介入肿瘤的生长,影响了肿瘤的新陈代谢,使其代谢速率减缓。在今后的研究中,将应用热物理研究方法定量研究乳腺肿瘤新陈代谢与外界能量之间的关系。     

利用CRISPR/Cas9技术构建永生化脐带间充质干细胞系及MYC-AS1转基因研究

人脐带间充质干细胞(hMSCs)是一种具有多向分化潜能的多能干细胞,在组织修复和某些疾病治疗的临床应用上发挥着重要作用.利用CRISPR/Cas9技术在腺相关病毒AAVS1位点插入具有磷酸甘油酸激酶PGK启动子和SV40-polyA的SV40 LT基因,使hMSCs达到永生化.并利用慢病毒构建具有抑癌作用的反义长链非编码RNA MYC-AS1转基因的hMSCs,从该细胞系的培养液中分离提取表达MYC-AS1的外泌体.通过处理肝癌HepG2细胞,研究外泌体对HepG2表型的影响.结果表明:与野生型MSCs相比,永生化细胞MSCs-SV40增殖显著加快,但其定向分化特性并未改变,可在体外稳定传代超过40代,且未发现成瘤性.MYC-AS1转基因hMSCs的外泌体能表达MYC-AS1,且显著抑制HepG2肿瘤细胞的增殖和迁移.这一研究通过CRISPR/Cas9技术敲入SV40LT基因成功构建了 hMSCs,其MYC-AS1转基因细胞的外泌体对HepG2肿瘤细胞具有明显的抑制作用,这对hMSCs及其外泌体的基础研究和临床应用研究具有重要意义.     

SDF-1/CXCR4拮抗剂AMD3100应用方面的研究进展

AMD3100是基质细胞衍生因子-1（SDF-1）受体CXCR4阻断剂,能有效阻断SDF-1/CXCR4轴的生理功能;SDF-1/CXCR4轴在介入干细胞动员、迁移、归巢,胚胎发育,免疫调节,炎症反应,免疫性疾病,HIV感染,肿瘤细胞的生长迁移等等方面起重要作用。AMD3100能够快速有效动员骨髓造血干细胞和间充质干细胞,抑制肿瘤细胞的生长和转移,阻断HIV-1感染T淋巴细胞的结合位点,抑制某些炎症性和免疫性疾病进展。因此对AMD3100的深入研究将有助于临床安全有效动员干细胞用于损伤组织的修复,能够为临床治疗HIV-1感染和某些肿瘤提供新的途径。该文综述了AMD3100应用方面的研究进展。     

细胞焦亡调控肿瘤免疫微环境的分子机制研究进展

为探究细胞焦亡在肿瘤免疫微环境中的分子机制,收集国内外最新文献资料,对小动物肿瘤现状、细胞焦亡、诱导细胞焦亡的蛋白家族和其在肿瘤免疫微环境中的作用机制进行阐述。结果表明:1)细胞焦亡是由Gasdermins(GSDMs)家族蛋白所介导的可调节的细胞程序性死亡,GSDMs被蛋白酶水解激活,切割形成N端(具有成孔活性),在细胞膜上打孔,导致渗透性细胞裂解,从而将促炎分子释放到细胞外,引发炎症和免疫反应,对肿瘤微环境的调节有重要意义;2)细胞发生焦亡时会不断胀大破裂,释放细胞内容物,其产生的炎性环境可以招募细胞毒性T细胞(CD8+T)、巨噬细胞和NK细胞等免疫细胞杀死和吞噬肿瘤细胞,抑制髓源性抑制细胞(MDSC);3)细胞焦亡将肿瘤免疫微环境激活为免疫刺激状态,使其由“冷”转“热”,抑制肿瘤细胞的增殖、侵袭、转移,靶向治疗肿瘤疾病,降低患病宠物的死亡率。综上,诱导细胞焦亡和调控肿瘤免疫微环境为抗肿瘤治疗提供了新思路,细胞焦亡分子生物学机制的深入研究有望为宠物临床提供一种前景广阔的新型治疗方法。     

大蒜素抗肿瘤的研究进展

大蒜素可以降低某些肿瘤的患病率。试验证明,大蒜素不仅能抑制致癌物的致癌作用,而且对肿瘤细胞的增殖也有抑制作用。目前的研究结果显示,大蒜素的抑癌机制为:抗氧化,抑制致癌物的形成,影响肿瘤细胞的细胞周期并诱导肿瘤细胞凋亡,增强机体免疫功能,对抗肿瘤药物有增敏作用等。     

Bone marrow stromal cells generate muscle cells and repair muscle degeneration

Bone marrow stromal cells (MSCs) have great potential as therapeutic agents. We report a method for inducing skeletal muscle lineage cells from human and rat general adherent MSCs with an efficiency of 89%. Induced cells differentiated into muscle fibers upon transplantation into degenerated muscles of rats and mdx-nude mice. The induced population contained Pax7-positive cells that contributed to subsequent regeneration of muscle upon repetitive damage without additional transplantation of cells. These MSCs represent a more ready supply of myogenic cells than do the rare myogenic stem cells normally found in muscle and bone marrow.     

茶氨酸溴香酰胺对人宫颈癌细胞体内外生长的抑制作用

将茶氨酸为母体合成的茶氨酸衍生物茶氨酸溴香酰胺(TBrC)与茶氨酸作比较,评估茶氨酸溴香酰胺对人宫颈癌细胞体内外生长的抑制作用与其分子机制。应用MTT等方法检测不同浓度的TBrC对人宫颈癌细胞体外生长的影响,运用蛋白质印迹法检测解析这些人宫颈癌细胞中与凋亡和生长密切相关蛋白的表达和药物可能的作用靶点。此外,通过建立动物肿瘤模型,评价TBrC对荷瘤裸鼠人宫颈癌生长的抑制效果。实验结果显示,TBrC抑制人宫颈癌细胞体内外生长的活性超过其母体化合物茶氨酸多倍,对小鼠生长无明显毒性;TBrC作用的分子机制之一可能与抑制VEGFR1-Bcl-2/Bax信号传导通路相关。研究结果提示,TBrC具有广泛应用于临床治疗和(或)辅助治疗人宫颈癌和其他癌症的潜力。     

Gene targeting in stem cells from individuals with osteogenesis imperfecta

Adult stem cells offer the potential to treat many diseases through a combination of ex vivo genetic manipulation and autologous transplantation. Mesenchymal stem cells (MSCs, also referred to as marrow stromal cells) are adult stem cells that can be isolated as proliferating, adherent cells from bones. MSCs can differentiate into multiple cell types present in several tissues, including bone, fat, cartilage, and muscle, making them ideal candidates for a variety of cell-based therapies. Here, we have used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in MSCs from individuals with the brittle bone disorder osteogenesis imperfecta, demonstrating successful gene targeting in adult human stem cells.     

Phagocytosis of Candida albicans enhances malignant behavior of murine tumor cells

Murine tumor cells were induced to phagocytize either Candida albicans or group A streptococcal cells. The presence of microbial particles within the tumor cell cytoplasm had no effect on in vitro tumor cell growth. However, when Candida albicans-infected tumor cells were injected into syngeneic mice, they formed tumors that grew faster, invaded the surrounding normal tissue more rapidly and metastasized more rapidly than control tumor cells. Tumor cells infected with group A streptococcal particles did not grow faster or show increased malignant behavior. These data indicate that the in vivo behavior of malignant tumor cells can be modulated by microbial particles, which are often present in the microenvironment of the growing tumor.     

Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro

Modulation of the growth of human and murine cell lines in vitro by recombinant human tumor necrosis factor-alpha (rTNF-alpha) and recombinant human interferon-gamma (rIFN-gamma) was investigated. rTNF-alpha had cytostatic or cytolytic effects on only some tumor cell lines. When administered together with rIFN-gamma, rTNF-alpha showed enhanced antiproliferative effects on a subset of the cell lines tested. In contrast to its effects on sensitive tumor cells, rTNF-alpha augmented the growth of normal diploid fibroblasts. Variations in the proliferative response induced by rTNF-alpha were apparently not due to differences in either the number of binding sites per cell or their affinity for rTNF-alpha. These observations indicate that the effects of rTNF-alpha on cell growth are not limited to tumor cells, but rather that this protein may have a broad spectrum of activities in vivo.     

Tumor growth need not be driven by rare cancer stem cells

The cancer stem cell hypothesis postulates that tumor growth is driven by a rare subpopulation of tumor cells. Much of the supporting evidence for this intriguing idea is derived from xenotransplantation experiments in which human leukemia cells are grown in immunocompromised mice. We show that, when lymphomas and leukemias of mouse origin are transplanted into histocompatible mice, a very high frequency (at least 1 in 10) of the tumor cells can seed tumor growth. We suggest that the low frequency of tumor-sustaining cells observed in xenotransplantation studies may reflect the limited ability of human tumor cells to adapt to growth in a foreign (mouse) milieu.     

Immunotherapy of cancer: immunospecific rejection of tumors in recipients of neuraminidase-treated tumor cells plus BCG

Firmly established methylcholanthrene fibrosarcomas in syngeneic mice will totally disappear if the hosts are treated with living tumor cells that have been exposed to Vibrio cholerae neuraminidase in vitro. The effect is magnified by the simultanieous injection of a nonspecific immunostimulant, BCG. The rejection of the methylcholanthrene tumor is immunospecific and can be induced only with tumor cells, treated with Vibrio cholerae neuraminidase, identical in type with the growing tumor.     

Gastric cancer originating from bone marrow-derived cells

Epithelial cancers are believed to originate from transformation of tissue stem cells. However, bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. We show that although acute injury, acute inflammation, or transient parietal cell loss within the stomach do not lead to BMDC recruitment, chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, induces repopulation of the stomach with BMDCs. Subsequently, these cells progress through metaplasia and dysplasia to intraepithelial cancer. These findings suggest that epithelial cancers can originate from marrow-derived sources and thus have broad implications for the multistep model of cancer progression.     

Primary bioassay of human tumor stem cells

A simple method has been developed to support human tumor stem cell colony growth in soft agar. The technique appears suitable for culture of a variety of neoplasms of differing histopathology. Tumor stem cell colonies arising from different types of cancer have differing growth characteristics and colony morphology. This bioassay should be suitable for clinical studies of effects of anticancer drugs or irradiation on human tumor stem cells.