肿瘤血管异质性及其研究意义

肿瘤血管异质性是抗肿瘤血管生成研究的理论基础.肿瘤血管与正常血管相比,其表现形式、发生基础均存在显著差异.深入研究肿瘤血管异质性有助于发现新的分子诊断标记和治疗靶点.     

肿瘤血管异质性及其研究意义

肿瘤血管异质性是抗肿瘤血管生成研究的理论基础。肿瘤血管与正常血管相比，其表现形式、发生基础均存在显著差异。深人研究肿瘤血管异质性有助于发现新的分子诊断标记和治疗靶点。     

核素标记小分子多肽靶向诊治肿瘤新生血管的应用研究进展

早期诊断、精准治疗可以明显改善恶性肿瘤患者的预后。有研究发现肿瘤新生血管不仅在肿瘤的发生发展中起着极其关键的作用,也是肿瘤诊治的重要靶点。特定序列的多肽可以特异地靶向肿瘤新生血管内皮细胞上的特定分子。放射性核素标记这类小分子多肽所制备的分子探针在肿瘤诊治方面具有优势。本文将以我们的研究成果为主,阐述放射性核素标记小分子多肽RGD及RRL在靶向肿瘤新生血管的显像与治疗方面的应用研究进展。      

肿瘤相关循环内皮细胞的分类标志物及其功能研究进展

经典肿瘤新生血管的形成主要包括血管生成(angiogenesis)和血管发生(vasculogenesis)、均依赖循环内皮细胞(circulating endothelial cells,CECs)的增殖、迁移、黏附而形成管腔.CECs不仅与血管新生和肿瘤生长、播散有关,还可能作为抗血管生成药物的靶点和反映疗效的标志物.循环内皮细胞膜上可表达多种表面分子,在从幼稚到成熟及活化过程要经历不同的阶段,而不同阶段细胞表达的表面分子有所不同.各表面分子在肿瘤血管新生过程中发挥重要作用.监测可靠的分子标志物量化CECs尤其是活化血管内皮细胞(activated circulating vascular endothelial cells,aCECs),来判定肿瘤新生血管和血管靶向治疗的疗效具有重要意义且已成为临床上的迫切需要.本文就肿瘤相关循环内皮细胞的分类、标志物及其功能做一综述.     

VEGF/VEGFR2信号通路调控机制的研究进展

血管生成贯穿恶性实体肿瘤发生发展的全过程,与肿瘤的发生发展、浸润转移以及预后不良密切相关。在促进恶性肿瘤血管生成的诸多因素中,血管内皮细胞生长因子(VEGF)与血管内皮细胞生长因子受体2(VEGFR2)构成的信号通路发挥着不可替代的作用,阻断该信号通路已成为肿瘤抗血管治疗的主要方法之一,然而有关该信号通路上游的分子调控机制尚不明确。本文对VEGF/VEGFR2信号通路分子调控机制的最新研究进展作一简要综述,以期为肿瘤抗血管靶向治疗提供新思路。     

Vasohibin-1与肿瘤

Vasohibin-1(VASH1)是新近发现的在血管内皮细胞中由血管内皮生长因子(VEGF)、成纤维生长因子-2(FGF-2)等诱导产生的具有负反馈调节血管生成作用的蛋白因子.近年来研究表明,VASH1在多种肿瘤血管生成中扮演着重要的角色,提示其有望成为相关肿瘤诊断和治疗的分子标志物以及分子靶向治疗的有效蛋白因子.     

微环境对肿瘤微血管内皮细胞异质性的影响

肿瘤微血管内皮细胞与正常组织来源的微血管内皮细胞相比，具有明显窗孔结构、对生长因子反应性高、粘附因子表达高等特点，是造成肿瘤血管通透性高且新生旺盛的重要原因，导致肿瘤的快速生长和转移。肿瘤微血管内皮细胞具有异质性，受宿主组织、肿瘤类型及肿瘤微环境的多重影响。了解肿瘤微血管内皮细胞发生、形态及功能上的异质性特点及其可能机制，对进行合理的、个性化的、以血管内皮细胞为靶的抗血管新生治疗意义重大。     

抗血管生成化疗的研究进展

肿瘤血管生成是肿瘤生长和转移的关键步骤,抑制肿瘤血管生成能有效达到抗肿瘤的目的。近年来,抗血管生成分子靶向治疗是研究热点。除此之外,传统细胞毒化疗药物以低剂量、频繁或持续、短间歇的方式给药亦可产生抗血管生成作用,此时,药物的靶点是肿瘤血管内皮细胞而非肿瘤细胞,这种治疗模式称为“抗血管生成化疗”。本文就近年来抗血管生成化疗的研究进展作一综述。     

肿瘤诊断和治疗的新载体：纤溶酶原Kringle 5

肿瘤生长和转移需要血管生成。纤溶酶原K5能够与血管内皮细胞特异性结合，并抑制血管内皮细胞增殖。此外，纤溶酶原K5分子量小。因此，通过放射性核素标记纤溶酶原K5，利用放射性核素的显像和治疗特性，结合纤溶酶原K5的血管抑制作用以及靶向肿瘤新生血管的特点，从而实现对肿瘤的显像和治疗。可见，对纤溶酶原K5进行放射性标记研究很有应用前景。     

小分子肿瘤血管阻断剂研究进展

肿瘤的生长和转移都依赖血管网的存在。肿瘤血管内皮细胞是抗肿瘤治疗的关键靶点之一。肿瘤血管靶向治疗有两种截然不同的模式,（1）抑制肿瘤新生血管生成;（2）阻断已有肿瘤血管。相应的药物称为血管阻断剂（vascular disrupting agents,VDAs）,分为抗体和小分子两类。小分子血管阻断剂是目前研究的热点。本文就小分子血管阻断剂的研究进展、用药策略及疗效评价进行综述。     

c-Met靶向成像在肿瘤诊断中的应用

肝细胞生长因子受体(c-Met)是一种酪氨酸激酶型受体，对于肿瘤的发生发展至关重要，c-Met靶向治疗已初步应用于临床，其对于癌症患者的治疗具有显著的益处。目前，由于无法对c-Met表达阳性的肿瘤患者进行有效的早期筛选，使得c-Met靶向治疗在肿瘤治疗中总体有效率偏低。c-Met靶向分子成像借助靶向分子成像探针能够实现肿瘤c-Met表达水平及活化状态的定量检测和直观揭示，对于肿瘤的早期诊断、治疗和预后具有重要意义和巨大的潜在价值。结合近年来c-Met靶向分子成像的研究，本文将深入分析、探讨c-Met靶向分子成像探针的构建及其在肿瘤诊断中的应用。     

Retargeting adenoviral vectors to improve gene transfer into tumors

Gene targeting to tumors using adenoviral (Ad) vectors holds great potential for cancer imaging and therapy, but the limited efficacy of current methods used to improve delivery to target tissues and reduce unwanted interactions remain substantial barriers to further development. Progress in characterizing the set of molecular interactions used by Ad vectors to infect particular tissues has aided the development of novel strategies for retargeting vectors to tumor cells. One method is chemical retargeting of adenovirus using bispecific antibodies (bsAbs) against both viral capsid proteins and tumor-specific cell surface molecules. This approach can be combined either with competitive inhibitors designed to reduce viral tropism in undesired tissues, or with traditional therapeutics to increase the expression of surface molecules for improved tumor targeting. Ablating liver cell-specific interactions through mutation of capsid proteins or chemical means are promising strategies for reducing adenovirus-induced liver toxicity. The nature of tumor neovasculature also influences Ad delivery, and the use of vascular disrupting agents (VDAs) such as combretastatin can help elucidate these contributions. In this investigation, we evaluate a variety of these methods for retargeting Ad vectors to tumor cells in vitro and in vivo, and assess the contributions of specific molecular and tissue interactions that affect Ad transgene delivery.     

Derlin-1 is overexpressed on the tumor cell surface and enables antibody-mediated tumor targeting therapy

PURPOSE: Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1 has been reported to participate in misfolded protein dislocation and integrates into the endoplasmic reticulum (ER) membrane to survey for such protein aggregates. We elucidate herein that Derlin-1 can leak to the plasmalemma from the ER in tumor cells and may have clinical application as a novel cancer target in the hope of developing a new tumor targeting therapy. EXPERIMENTAL DESIGN: The cell surface expression of Derlin-1 was shown by immunofluorescence analysis of nonpermeabilized cells and Western blotting of fractional proteins of tumor cells. Derlin-1 expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and gamma-scintigraphic imaging were done using (125)I-labeled Derlin-1 targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1 polyclonal antibody and monoclonal antibodies. RESULTS: Derlin-1 was expressed on various tumor cell surfaces and adopted a homodimer conformation. Robust cytoplasmic and membrane expression of Derlin-1 was detected in various types of human cancers tissues but was not correlated with any clinicopathologic features of pancreatic cancer. Derlin-1 directed antibodies specifically targeted to colon tumors and significantly suppress tumor growth in isogenic mice. CONCLUSIONS: These preclinical data show that Derlin-1 protein is a functional molecular target expressed on the tumor cell surface and is a candidate therapeutic target that may be translated into clinical applications.     

Novel surface targets and serum biomarkers from the ovarian cancer vasculature

The molecular phenotype of tumor vasculature is different from normal vasculature, offering new opportunities for diagnosis and therapy of cancer, but the identification of tumor-restricted targets remains a challenge. We investigated 13 tumor vascular markers (TVMs) from 50 candidates identified through expression profiling of ovarian cancer vascular cells and selected to be either transmembrane or secreted, and to be either absent or expressed at low levels in normal tissues while overexpressed in tumors, based on analysis of 1,110 normal and tumor tissues from publicly available Affymetrix microarray data. Tumor-specific expression of each TVM was confirmed at the protein level in tumor tissue and/or in serum. Among the 13 TVMs, 11 were expressed on tumor vascular endothelium; the remaining 2 TVMs were expressed by tumor leukocytes. Our results demonstrate that certain transmembrane TVMs such as ADAM12 and CDCP1 are selectively expressed in tumor vasculature and represent promising targets for vascular imaging or anti-vascular therapy of epithelial ovarian cancer, while secreted or shed molecules such as TNFRSF21/DR6 can function as serum biomarkers. We have identified novel tumor-specific vasculature markers which appear promising for cancer serum diagnostics, molecular imaging and/or therapeutic targeting applications and warrant further clinical development.     

单链抗体及其融合蛋白在肿瘤诊治中的应用

单链抗体由于分子量小,免疫原性低,组织穿透力强,特异性好等优点,与单克隆抗体相比,在肿瘤的诊断和治疗方面展示了更好的应用前景.全文对近年来单链抗体及其融合蛋白在肿瘤导向诊断和治疗,肿瘤基因治疗和肿瘤疫苗方面应用研究进展做一综述.     

Future developments in the selectivity of anticancer agents: Drug delivery and molecular target strategies

In the past, our limited understanding of the processes involved in the initiation and growth of cancer hindered our ability to effectively treat most human malignancies and therapies were often associated with significant toxic side effects as well as re-emergence of disease. The development of drug delivery systems such as liposomes has improved the specificity of various conventional anticancer agents by enhancing drug accumulation in tumors while often decreasing exposure to susceptible healthy tissues. More recently, the identification of a wide range of genes and corresponding protein products that are altered in various human cancers has revealed new molecular targets for cancer therapy that may provide improved selectivity for tumor cells over traditional cytotoxic agents. This review discusses how advances in the sophistication of liposomal delivery systems may open new opportunities for combining novel molecular targeting strategies with pharmacological targeting via liposomes to optimize the therapy of many human malignancies.     

肿瘤乏氧分子靶向治疗

乏氧是多数实体瘤的固有特征之一,可增加肿瘤细胞对放化疗的耐受性、促使肿瘤血管生成,是重要的不良预后因素.靶向杀伤肿瘤内的乏氧细胞成为肿瘤治疗的热点.生物还原性药物可通过特定的还原反应激活为细胞毒性代谢产物进而杀伤乏氧肿瘤细胞,而小分子靶点抑制剂则选择性地作用于乏氧途径中的关键环节,二者为肿瘤的乏氧靶向治疗开辟了新的途径.     

靶向uPA-uPAR系统在肿瘤治疗中的研究进展

uPA-uPAR系统在多种肿瘤组织中表达增高,该系统不但可促进细胞外基质蛋白降解,而且可以与玻连蛋白、整合素等结合参与细胞内信号转导,从而介导肿瘤的发生与发展。近年来,一系列靶向uPA-uPAR系统的方案在肿瘤治疗中取得了显著效果,并且其中部分药物已经进入临床试验阶段,为肿瘤的靶向治疗提供了新思路。本文拟从靶向uPA-uPAR系统的基因治疗、药物治疗和免疫治疗等方面的研究进展进行综述。     

Eradication of established renal cell carcinoma by a combination of 5-fluorouracil and anti-4-1BB monoclonal antibody in mice

Renal cell carcinoma (RCC), one of the most incurable malignancies, is highly resistant to chemotherapy and radiotherapy. Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB monoclonal antibody (mAb) has been shown to induce regression of several animal tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug, 5-fluorouracil (5-FU), has little effect on established RCC, Renca tumors, but combination therapy with anti-4-1BB mAb and 5-FU eradicates the tumors in more than 70 % of mice. The regressing tumor tissues from mice receiving the combination therapy contained more apoptotic tumor cells and tumor infiltrating lymphocytes than tumor tissues from mice receiving 5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and tumor- draining lymph nodes (TDLNs) of the combination therapy mice was greatly increased compared to that of control or 5-FU monotherapy mice. Mice that had recovered due to the combination therapy rapidly rejected rechallenge with the tumor, pointing to the establishment of long-lasting tumor-specific memory. Our results indicate that targeting tumors with 5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC.     

Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells

Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26-tumor-bearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors.