Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

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Misbehaviour of XIST RNA in Breast Cancer Cells

A role of X chromosome inactivation process in the development of breast cancer have been suggested. In particular, the relationship between the breast cancer predisposing gene BRCA1 and XIST, the main mediator of X chromosome inactivation, has been intensely investigated, but still remains controversial. We investigated this topic by assessing XIST behaviour in different groups of breast carcinomas and in a panel of breast cancer cell lines both BRCA1 mutant and wild type. In addition, we evaluated the occurrence of broader defects of heterochromatin in relation to BRCA1 status in breast cancer cells. We provide evidence that in breast cancer cells BRCA1 is involved in XIST regulation on the active X chromosome, but not in its localization as previously suggested, and that XIST can be unusually expressed by an active X and can decorate it. This indicates that the detection of XIST cloud in cancer cell is not synonymous of the presence of an inactive X chromosome. Moreover, we show that global heterochromatin defects observed in breast tumor cells are independent of BRCA1 status. Our observations sheds light on a possible previously uncharacterized mechanism of breast carcinogenesis mediated by XIST misbehaviour, particularly in BRCA1-related cancers. Moreover, the significant higher levels of XIST-RNA detected in BRCA1-associated respect to sporadic basal-like cancers, opens the possibility to use XIST expression as a marker to discriminate between the two groups of tumors.     

Optimization of Phase-Change Contrast Agents for Targeting MDA-MB-231 Breast Cancer Cells

Breast cancer remains a leading cause of death for women throughout the world. Recent advances in medical imaging technologies and tumor targeting agents signify vast potential for progress toward improved management of this global problem. Phase-change contrast agents (PCCAs) are dynamic imaging agents with practical applications in both the research and clinical settings. PCCAs possess characteristics that allow for cellular uptake where they can be converted from liquid-phase PCCAs to gaseous microbubbles via ultrasound energy. Previously, we reported successful internalization of folate-targeted PCCAs in MDA-MB-231 breast cancer cells followed by ultrasound-mediated activation to produce internalized microbubbles. This study examines the binding, internalization and activation of folate-receptor targeted PCCAs in MDA-MB-231 breast cancer cells as a function of gaseous core compositions, incubation time and ultrasound exposure period. In vitro results indicate that internalization and ultrasound-mediated activation of PCCAs were significantly greater using a 50:50 mixture of decafluorobutane:dodecafluoropentane compared with other core compositions: 50:50 octafluoropropane:decafluorobutane (p < 0.0001), decafluorobutane (p < 0.04) and dodecafluoropentane (p < 0.0001). Furthermore, it was found that PCCAs composed of perfluorocarbons with higher boiling points responded with greater activation efficiency when exposed to 12 s of ultrasound exposure as opposed to 4 s of ultrasound exposure. When evaluating different incubation times, it was found that incubating the PCCAs with breast cancer cells for 60 min did not produce significantly greater internalization and activation compared with incubation for 10 min; this was concluded after comparing the number of microbubbles present per cell before ultrasound versus post-ultrasound, and finding a ratio of intracellular microbubbles post-ultrasound/pre-ultrasound, 3.46 versus 3.14, respectively. The data collected in this study helps illustrate further optimization of folate-receptor targeted PCCAs for breast cancer targeting and imaging.     

肿瘤干细胞与肿瘤转移

肿瘤干细胞具有不断自我更新、抗凋亡和耐药等特性,随着肿瘤干细胞（或干细胞样肿瘤细胞）研究的不断深入,它在肿瘤发生发展中的作用及其临床治疗价值日益显现。本文就肿瘤干细胞发现的历史、调节机制及其在肿瘤转移中的作用作一综述。     

Hypothalamic Gene Transfer of BDNF Inhibits Breast Cancer Progression and Metastasis in Middle Age Obese Mice

Activation of the hypothalamus-adipocyte axis is associated with an antiobesity and anticancer phenotype in animal models of melanoma and colon cancer. Brain-derived neurotrophic factor (BDNF) is a key mediator in the hypothalamus leading to preferential sympathoneural activation of adipose tissue and the ensuing resistance to obesity and cancer. Here, we generated middle age obese mice by high fat diet feeding for a year and investigated the effects of hypothalamic gene transfer of BDNF on a hormone receptor-positive mammary tumor model. The recombinant adeno-associated viral vector-mediated overexpression of BDNF led to marked weight loss and decrease of adiposity without change of food intake. BDNF gene therapy improved glucose tolerance, alleviated steatosis, reduced leptin level, inhibited mouse breast cancer EO771 growth, and prevented the metastasis. The reduced tumor growth in BDNF-treated mice was associated with reduced angiogenesis, decreased proliferation, increased apoptosis, and reduced adipocyte recruitment and lipid accumulation. Moreover, BDNF gene therapy reduced inflammation markers in the hypothalamus, the mammary gland, the subcutaneous fat, and the mammary tumor. Our results suggest that manipulating a single gene in the brain may influence multiple mechanisms implicated in obesity-cancer association and provide a target for the prevention and treatment of both obesity and cancer.     

乳腺癌骨转移特点的分析

目的　探讨乳腺癌的骨转移特点。方法　对 5 72例乳腺癌患者进行了 99m Tc- MDP全身骨显像 ,并对阳性结果及转移部位进行了分析。结果　 5 72例乳腺癌患者发现 186例转移 ,转移率达 32 .5 %;转移病灶共 32 7处 ,其中 31例为单发灶 ,占总病灶数的 16 .7%。各病理类型及临床各期患者骨转移均好发于脊柱 ,与其它部位比较有极显著差异 (P<0 .0 1)。结论　乳腺癌骨转移发生早且转移率高 ;骨转移的发生与临床分型、病理类型无明显关系。     

Twist基因与乳腺癌的发生和转移

乳腺癌是来源于乳腺终末导管小叶单元上皮的恶性肿瘤,多发生于中老年女性,是目前威胁女性健康常见的疾病之一。其发病率在过去的几十年中逐年增高,已跃居女性恶性肿瘤的首位。近年来的研究发现,Twist作为一种肿瘤相关基因,其在乳腺癌的发生、发展以及诊断、治疗和预后中起着重要作用。     

TRAIL联合Res对乳腺癌MDA-MB-231细胞DR和Caspase表达的影响

目的研究TRAIL联合白藜芦醇（Res）对乳腺癌MDA-MB-231细胞DR和caspase表达的影响。方法MTT法检测细胞增殖;流式细胞术检测细胞凋亡及细胞表面DR4、DR5蛋白的表达;分光光度法检测caspase-3、caspase-8相对活性;荧光定量PCR检测DR4、DR5及caspase-3、caspase-8 mRNA的表达。结果50μmol／L和100μmo/L,Res分别与50ng／mL TRAIL联合作用后,对MDA-MB-231细胞增殖的抑制率及细胞凋亡率分别与单独应用相应浓度的Res和TRAIL比较,均存在显著差异（P〈0．01）。50μmol／L和100μmol／LRes分别与50ng／mLT RAIL联合作用后,caspase-3、caspase-8的相对活性与对照组及单用TRAIL、Res比较均明显增强,差异显著（P〈0．01）。Res作用后,细胞表面DR4、DR5荧光指数与对照组比较明显增强。荧光定量PCR结果显示与对照组比较．Res作用后DR4、DR5mRNA表达上调;与单独用药比较,TRAIL联合Resetcagpase-3、easpase-8 mRNA表达上调。结论TRAIL和Res联合应用对诱导乳腺癌MDA-MB-231细胞凋亡具有明显的协同效果,其作用机制可能与增加DR和caspase活性有关。     

Orthotopic Expression of Noggin Protein in Cancer Cells Inhibits Human Lung Carcinoma Growth In Vivo

Purpose

We explored the effect of Noggin protein expression on tumor growth in vivo by using fluorescence imaging.

Procedures

Human lung carcinoma MV522 cells were transduced by using bicistronic (EGFP/Nog) or a control (EGFP) lentivirus at >95% efficacy. The transduced cells were implanted in athymic mice either individually or after mixing with DsRed2-expressing MV522 cells.

Results

The expression of Noggin protein was demonstrated in EGFP+/Nog+ but not in EGFP+ cell lysates and conditioned media. Noggin did not inhibit tumor cell proliferation in vitro. Implantation of EGFP+ resulted in rapid tumor growth, whereas mice implanted with EGFP+/Nog+ either failed to develop tumors or developed smaller slowly proliferating ones. In the case of tumors grown from mixtures with DsRed2+ cells, only Noggin-expressing cells resulted in decreased tumor volumes with low vascular density and poorly developed stroma.

Conclusion

The effect of Noggin protein expression is a consequence of inhibition of stromal and/or endothelial proliferation in vivo.     

NONO Inhibits Lymphatic Metastasis of Bladder Cancer via Alternative Splicing of SETMAR

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Oral Vaccination With Adeno-associated Virus Vectors Expressing the Neu Oncogene Inhibits the Growth of Murine Breast Cancer

Recombinant adeno-associated viruses (AAV) have been used for therapeutic gene transfer. These vectors offer a number of advantages including resistance to the effects of pH, a broad cellular tropism, efficient gene transfer, persistence of gene expression, and little toxicity. AAV vectors; however, at high doses can induce humoral and cellular immune responses. While potentially problematic for replacement gene therapy, this effect may be advantageous for antitumor vaccination. We examined the activity of an oral and intramuscular antitumor vaccination using AAV serotypes 5 and 6 expressing a truncated neu oncogene in a neu-positive murine TUBO breast cancer model. Mice receiving a single oral administration of AAV5-neu or AAV6-neu demonstrated improved survival. Oral vaccination significantly improved survivals compared with intramuscular vaccination. Mice vaccinated with AAV6-neu survived longer than those treated with AAV5-neu. Vaccination with AAV5-neu or AAV6-neu induced both humoral and cellular immune responses against the NEU antigen. These responses were more robust in the mice undergoing oral vaccination compared with mice receiving the intramuscular vaccination. Protection from tumor was long lasting with 80% of the animals treated with oral AAV6-neu surviving a re-challenge with TUBO cells at 120 and 320 days post-vaccination. Further evaluation of AAV-based vectors as tumor vaccines is warranted.     

雷帕霉素抑制人肾癌ACHN细胞生长及转移的实验研究

[目的]观察雷帕霉素（RPM）对人肾癌细胞株ACHN生长、周期、凋亡及转移的影响,探讨RPM抑制肾癌细胞生长、转移的可能机制及临床应用前景.[方法]体外培养肾癌ACHN细胞,用不同浓度（10 ng/mL、25 ng/mL）的RPM干预ACHN细胞.采用MTT法检测RPM对于ACHN细胞增殖的影响;流式细胞仪检测ACHN细胞周期及凋亡的变化;Transwell 小室法检测细胞体外侵袭能力的变化;动物体内荷瘤实验检测对ACHN侵袭转移的影响.[结果]RPM能显著抑制ACHN细胞生长增殖,且呈时间和浓度依赖性,差别有显著性意义（P〈0.05）,并促进肿瘤细胞的早期凋亡（P〈0.05）.[结论]RPM明显抑制人肾癌ACHN细胞的生长及迁移,以RPM为基础的肾癌治疗方案可能在临床中具有良好的应用前景.     

KISS-1基因与乳腺癌转移的关系

近年来,乳腺癌在我国的发病率不断上升,乳腺癌的侵袭、转移是治疗失败与患者病死的主要原因.由于肿瘤的侵袭、转移是一个多因素、多步骤的过程,所以虽然目前对其进行了大量的研究与探索,其调节机制仍不十分明了.近年来发现,KISS-1基因与多种实体肿瘤转移相关,其在乳腺癌中的作用尚存在争议,本文就该基因在乳腺癌转移中的研究作一综述.     

针对人c-Met基因的RNA干扰对晶状体上皮细胞增殖的影响

目的 探讨针对肝细胞生长因子(HGF)受体c-Met的RNA干扰对人晶状体上皮细胞增殖的影响.方法 构建针对人c-Met基因的小干扰RNA(siRNA),转染体外培养的人晶状体上皮细胞,利用实时荧光定量聚合酶链反应(Real-Time PCR)检测细胞中c-Met mRNA的表达变化,应用MTT法检测HGF诱导后人晶状体上皮细胞增殖.结果 与对照组相比,转染后的人晶状体上皮细胞中c-Met mRNA表达水平明显下降(P《0.01);与单纯HGF诱导组相比,转染后HGF诱导的人晶状体上皮细胞生长明显减慢,增殖能力明显下降(P《0.01).结论 针对人c-Met基因的RNA干扰可以有效阻断人晶状体上皮细胞中c-Met mRNA的表达,并能抑制HGF诱导的人晶状体上皮细胞的增殖.     

乳腺癌肝转移的介入治疗

目的:评价乳腺癌肝转移介入治疗疗效,探讨其在乳腺癌肝转移综合治疗中的价值。方法:2000—2005年对68例乳腺癌肝转移患者共进行156次介入治疗,其中61例行超液化碘油栓塞。结果:应用世界卫生组织(WHO)实体瘤疗效评定标准评估治疗后疗效,68例中完全缓解(CR)0例(0%),部分缓解(PR)37例(54.41%),稳定(SD)26例(38.24%),进展(PD)5例(7.35%)。总客观有效率为54.41%。中位生存期为14个月,中位病灶稳定持续时间为9个月。6个月、l年、2年累积生存率分别为:92.60%、55.90%和17.00%。结论:乳腺癌肝转移的介入治疗疗效显著,毒副作用小,可以作为乳腺癌肝转移综合治疗中的主要治疗手段。     

乳腺癌组织中Galectin-3表达与淋巴转移关系的探讨

【目的】探讨半乳糖凝集素－3（Galectin－3）在乳腺良、恶性病变组织中的表达及其与淋巴转移的关系。【方法】采用免疫组织化学E1iVision法检测139例乳腺良、恶性病变组织中Galectin－3的表达情况,比较有、无淋巴结转移乳腺癌组织中Galectin-3的表达。【结果】Galeetin－3在乳腺恶性病变组织中阳性表达率（91．4％）明显高于良性病变（33．33％）,差异有显著性（P〈0．01）;伴有淋巴结转移乳腺癌组织的阳性表达率（97．83％）高于不伴有淋巴转移（81．82％）乳腺癌组织,差异有显著性（P〈0．05）;而且有淋巴结转移的Galectin-3阳性表达多呈中、强阳性,Galectin-3表达与淋巴结转移呈正相关（rs=0．521,P〈0．05）。【结论】Galectin-3在乳腺恶性病变中的表达明显高于良性病变中的表达,随着肿瘤的侵袭、淋巴转移,其表达强度逐渐增强。其对预测乳腺癌的发展及而后判断有泰者价值．     

Optical Redox Imaging Detects the Effects of DEK Oncogene Knockdown on the Redox State of MDA-MB-231 Breast Cancer Cells

Molecular Imaging and Biology - Optical redox imaging (ORI), based on collecting the endogenous fluorescence of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp)...