病毒治癌研究进展

病毒用于恶性肿瘤的治疗近20年发展尤为迅速，已成为当今肿瘤治疗研究的热点之一。到目前为止，至少有10种不同的病毒已经进入或不久将进入临床试验。动物实验和临床试验都得到了一些令人鼓舞的结果。简要综述病毒治癌的历史与现状，安全性与有效性等。     

病毒治癌研究进展

病毒用于恶性肿瘤的治疗近20年发展尤为迅速，已成为当今肿瘤治疗研究的热点之一。到目前为止，至少有10种不同的病毒已经进入或不久将进入临床试验。动物实验和临床试验都得到了一些令人鼓舞的结果。简要综述病毒治癌的历史与现状、安全性与有效性等。     

放疗的致癌作用

放疗是治疗恶性肿瘤的重要手段之一，随着放疗技术的不断改进和综合治疗效果的提高，患者生存时间延长，使放疗致癌作用成为一些治愈患者长期生存的威胁之一。虽然三维适形放疗和IMRT放疗的应用提高了靶区剂量及肿瘤局部控制率，并减少了邻近重要器官的并发症，但IMRT增加了机器输出量，延长了每次射线作用时间并增加了照射野数目。这不可避免地使得大量正常组织受到低剂量照射，由此引发了另一方面的顾虑，即这些技术是否存在原发肿瘤治愈后增加了辐射致癌的可能性。现就放疗的致癌作用讨论如下。     

镍的致癌作用

镍的致癌作用启东肝癌防治研究所（启东市２２６２２００）顾公望，陆东东７Ｏ年代有直接证据表明，镍是一种必需的微量元素。镍的生物学作用，可能与其参与机体的代谢有关，在ＤＮＡ、ＲＮＡ的结构和功能中起一定的作用。动物实验显示了缺镍影响动物的生长、繁殖和造血，...     

“癌基因”和化学致癌作用

Oncogene来自希腊语onkos一词,在我国译为“癌基因”,“致癌基因”、“癌化基因”等。显然,人们对“癌基因”的认识还刚刚开始。     

EB病毒相关胃癌研究进展

Epstien-Barr病毒(EBV)在EBV阳性胃癌的演进中有重要作用.最近的研究集中在本病的流行病学和生物学发病机制.复习近年来针对EBV相关胃癌有关的基础、临床和流行病学研究,讨论EBV在胃癌发生发展中的作用,介绍此领域最新的研究成果.     

细颗粒物2.5致癌作用的研究进展

大气细颗粒物（PM）2.5来源广泛,组成成分复杂,其表面积较大,可与有害物质结合,通过直接摄入、皮肤接触、呼吸作用等途径进入人体,对人体健康造成严重危害。PM2.5可通过诱导细胞氧化应激、炎症反应等,造成组织损伤、纤维化,促进肿瘤的发生发展。近年来的研究表明,长期暴露于PM2.5污染的空气中,人类呼吸系统、心血管系统以及肿瘤等疾病的负担日益增加,PM2.5对健康的影响应该引起人们的重视。本文对PM2.5的致癌成分、致癌作用以及PM2.5暴露与肿瘤发生发展的关系进行综述,以期为PM2.5致癌机制的研究和肿瘤防治工作提供参考。     

白血病病毒病因的现代观

20世纪70年代,已有研究证明逆转录病毒可诱发动物白血病,后续研究发现人类基因组有大量内源性逆转录病毒,但是仅在局部地区有逆转录病毒相关的成人T细胞白血病（adult T-cell leukemia,ATL）流行。近年来,对APOBEC3（apolipoprotein B mRNA editing enzyme catalytic polypeptide 3）成员的深入研究阐释了人类对逆转录病毒诱发白血病的抵御机制。EB病毒（Ep-stein-Barr virus,EBV）在人群中广泛传播,以隐性感染形式长期存在于体内,与部分淋巴瘤的发生、发展密切相关,部分实体瘤也与EBV相关,表明其致瘤性。其他病毒感染与人类白血病/淋巴瘤发生、发展的关系,部分可能通过复杂、曲折的网络关系间接相关,大部分还有待于进一步的深入研究。      

治疗癌症的新途径—病毒

将病毒修饰或改构后,利用其攻击肿瘤细胞的特点起到抗肿瘤作用,目前已成为探索肿瘤治疗的新途径。     

Caprine herpesvirus 1 (CpHV-1) as a potential candidate for oncolytic virotherapy

Caprine Herpesvirus type 1 (CpHV-1) is a species-specific herpes virus able to induce apoptosis in several biological systems. In the present study we aimed to investigate the ability of CpHV-1 to reduce cells viability, to replicate and to cause cell death also in human cancer cell lines. We tested the CpHV-1 effects on HEL-299, Vero, MDA-MB-468, HeLa, U2OS, PC3, A549 and K562 neoplastic cell lines and on MDBK cells. Firstly, we evaluated the effect of CpHV-1 infection on cell viability by MTT assay and our data showed that CpHV-1 can induce a marked cytopathic effect (CPE) in most of cell lines tested, except for HEL-299, Vero and K562 cells. The reduction of cell viability was associated with a significant increase of viral production. We next investigated if CpHV-1 was able to induce cell death and so through western blotting analysis we evaluated cleaved caspase 3, LC3II and p62 protein levels after infection. Caspase 3 activation was detected in MDBK cells and, even if at different times p.i., also in MDA-MB-468, U2OS, and PC3 cell lines, while LC3II increase and concomitant p62 protein reduction were observed only in U2OS, and A549 cells, no significant alteration of these proteins was observed in the other cell lines tested. Finally, to confirm virus ability to trigger apoptosis we performed an Annexin-V apoptosis test after 24 h p.i.

Although we need to further explore mechanisms underlying CpHV-1 treatment, this study could serve as the basis for the development of new treatment options aiming to fight several cancer types.     

Immune response elicited in the tumor microenvironment upon rMV-SLAMblind cancer virotherapy

Oncolytic virotherapy is a promising therapy for cancer. We previously established a recombinant measles virus (rMV-SLAMblind) that targets NECTIN4-expressing cancer cells and demonstrated its antitumor effects using a xenograft model in an immunodeficient mouse. In the current study, to investigate the immune response after rMV-SLAMblind therapy, we developed an immunocompetent cancer mouse model by introducing the NECTIN4 gene into mouse cancer cell lines. NECTIN4-expressing mouse cancer cells were successfully killed by rMV-SLAMblind in vitro. After transplantation of the NECTIN4-expressing tumor cells, rMV-SLAMblind significantly suppressed tumor growth in immunocompetent mice. Thus, this immunocompetent mouse cancer model could be a powerful tool in which to study the effect of rMV-SLAMblind therapy on the immune response. Using this model we found that rMV-SLAMblind elicited significant activation of natural killer cells, type 1 helper T cells and the tumor-specific CD8⁺ T-cell response in the tumor microenvironment. Immune cell depletion study revealed that CD8⁺ cells particularly played significant roles in the therapeutic efficacy of rMV-SLAMblind. Thus, rMV-SLAMblind exerts a therapeutic effect, not only directly by tumor cell killing, but also indirectly by efficient induction of antitumor immunity.     

Mesenchymal stem cell carriers enhance anti-tumor efficacy of oncolytic virotherapy

Oncolytic viruses (OVs) specifically infect, replicate and eventually destroy tumor cells, with no concomitant toxicity to adjacent normal cells. Furthermore, OVs can regulate tumor microenvironments and stimulate anti-tumor immune responses. Mesenchymal stem cells (MSCs) have inherent tumor tropisms and immunosuppressive functions. MSCs carrying OVs not only protect viruses from clearing by the immune system, but they also deliver the virus to tumor lesions. Equally, cytokines released by MSCs enhance anti-tumor immune responses, suggesting that MSCs carrying OVs may be considered as a promising strategy in enhancing the anti-tumor efficacies of virotherapy. In the present review, preclinical and clinical studies were evaluated and discussed, as well as the effectiveness of MSCs carrying OVs for tumor treatment.     

Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors

BackgroundPrevious studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure.MethodsCell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed.ResultsvvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors.ConclusionsOncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.     

Oncolytic virotherapy enhances the efficacy of a cancer vaccine by modulating the tumor microenvironment

The efficacy of cancer vaccines has been limited by the immunosuppressive tumor microenvironment, which can be alleviated by immune checkpoint inhibitor (ICI) therapy. Here, we tested if oncolytic viruses (OVs), similar to ICI, can also synergize with cancer vaccines by modulating the tumor microenvironment. VSV-GP, a chimeric vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of the lymphocytic choriomeningitis virus, is a promising new OV candidate. Here, we show that in mouse B16-OVA melanoma, combination treatment of VSV-GP with an ovalbumin (OVA) peptide-loaded dendritic cell (DC) vaccine (DCVacc) significantly enhanced survival over the single agent therapies, although both DCVacc and DCVacc/VSV-GP treatments induced comparable levels of OVA-specific CD8 T cell responses. Virus replication was minimal so that direct viral oncolysis in B16-OVA did not contribute to this synergism. The strong therapeutic effect of the DCVacc/VSV-GP combination treatment was associated with high numbers of tumor-infiltrating, highly activated T cells and the relative reduction of regulatory T cells in treated and contra-lateral nontreated tumors. Accordingly, depletion of CD8 T cells but not natural killer cells abrogated the therapeutic effect of DCVacc/VSV-GP supporting the crucial role of CD8 T cells. In addition, a drastic increase in several proinflammatory cytokines was observed in VSV-GP-treated tumors. Taken together, OVs, similar to ICI, have the potential to markedly increase the efficacy of cancer vaccines by alleviating local immune suppression in the tumor microenvironment.     

Viral therapy for pancreatic cancer: Tackle the bad guys with poison

Pancreatic cancer is one of the most devastating diseases with very poor prognosis. Only a small proportion is curable by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Therefore, there is an urgent need for the development of novel therapeutic approaches to improve the patient outcome. Recently the viral therapy is emerging as a novel effective therapeutic approach for cancer with the potential to selectively treat both primary tumor and metastatic lesions. This review provides an overview of the current status of viral treatment for pancreatic cancer, both in the laboratories and in clinical settings.     

整联蛋白连接激酶及其异常与肿瘤发生的研究进展

编码细胞表面受体和细胞内蛋白激酶的基因突变一直被视为肿瘤发生的关键制约点。整联蛋白连接激酶（integrin-linkedkinase,ILK）作为蛋白-蛋白相互作用网络中的一个集结点,通过其偶联的信号通路,在调节细胞的生物学功能上展现了显著的多面效应。迄今,多种肿瘤中已相继报道ILK呈过表达,然而ILK在少部分肿瘤中的表达情况也有待进一步研究澄清。ILK作为一个很有潜力的研究基点与肿瘤发生发展的紧密联系值得深入探讨。     

Oncolytic Viral Therapy for Human Prostate Cancer by Conditionally Replicating Herpes Simplex Virus 1 Vector G207

Over the last few years, a conditionally replicating herpes simplex virus 1 (HSV-1) vector, G207 has been used for the treatment of several malignant tumors. In this article we evaluate the antitumoral effect of G207 against prostate cancer in vitro and in vivo . The susceptibility of the human prostate cancer cell lines, DU145 and PC3 to G207 at a multiplicity of infection (MOI) of 0.1 was examined. In addition, the growth characteristics of G207 were assessed. Athymic mice with s.c. tumors were inoculated in vivo intraneoplastically with 1x10⁷ plaque-forming units (PFU) of G207. For the pathological analyses, s.c. tumors were stained with X-gal. DU145 and PC3 were efficiently destroyed by G207 within 7 days. The viral yields of G207 increased time-dependently. In vivo , the intraneoplastic inoculation of G207 induced a significant inhibition of the tumor growth. The mean tumor growth ratio was significantly inhibited in the G207-treated tumors (DU145, P < 0.0001; PC3, P < 0.001 versus controls). In a pathological study, many lacZ -positive cells were diffusely present in the G207-treated tumors. G207 showed a significant antitumoral effect against human prostate cancer cell lines, and thus may be considered a useful agent for the treatment of prostate cancer.     

Viral oncogenesis and the immune system

Oncogenic transformation of normal cells and the establishment of transformed cells to form malignant tumors is a complex, multistep process influenced by viruses in multiple ways. The relationship between viruses and the immune system manifests itself, in part, through various roles of viruses in transformation of host cells, including cells of the immune system. A large number of viruses participate in oncogenic transformation of cells in many animal species. Candidates for oncogenic transformation in man are human T lymphotropic viruses I and II, certain human papillomavirus types, hepatitis B virus, and Epstein-Barr virus. Various mechanisms, which may overlap with one another, have been proposed to account for viral oncogenesis. These include introduction of a directly transforming viral gene, retroviral transduction of protooncogenes, mutagenesis, uncoupling of cellular protooncogene expression from normal regulatory controls, overexpression of normal cellular genes resulting from effects of viral cis- or trans-acting factors, and inactivation of tumor suppressor genes. A second critical area of interaction between viruses and the immune system is in the selection of transformed cells. When cell transformation is accompanied by expression of tumor antigens, the immune system may influence tumor cell establishment and selection of transformed cells for metastatic outgrowth. Finally, host well-being may be severely compromised when viruses infect cells of the immune system, leading to an inability to mount immunological responses specific for opportunistic microorganisms and for cells transformed by viruses or nonviral agents. Human immunodeficiency virus infection exemplifies this phenomenon, although other viruses also negatively affect the immune system. The role of normal immune responses in limiting tumor cell growth is evident from the increased incidence of malignancies in immunocompromised hosts.