Prevention of Tumor Progression by a Novel Approach

通过新方法预防肿瘤进展

基本信息

批准号：
8461064
负责人：
FAZLUL H. SARKAR
金额：
$ 29.65万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461064
关键词：
Adverse effects Animal Model Biochemical Pathway Biological Biological Availability Cancer Etiology Cancer Patient Cell Survival Cells Cessation of life Clinical Data Curcumin DNA Binding Data Development Diagnosis Dinoprostone Disease Down-Regulation Drug resistance E-Cadherin Epithelial Future Gene Expression Genistein In Vitro Induction of Apoptosis Investigation Isoflavones Laboratories Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal Metabolism MicroRNAs Mission Modality Molecular Names Neoplasm Metastasis Oncogenes Outcome PTEN gene PTGS2 gene Pancreas Pathway interactions Patients Phenotype Plant Roots Plasma Prevention Publications Publishing Recurrence Regulation Resistance Role Signal Pathway Signal Transduction Staging Testing Therapeutic Time Tissues Transgenic Animals Transgenic Organisms United States United States National Institutes of Health Up-Regulation Vascular Endothelial Growth Factors Work Xenograft procedure analog angiogenesis base cancer stem cell carcinogenesis cell type chemotherapeutic agent conditioning design epithelial to mesenchymal transition gemcitabine improved in vivo insight killings migration notch protein novel novel strategies pancreatic cancer cells pre-clinical prevent stem tumor tumor progression volunteer

项目摘要

DESCRIPTION (provided by applicant): Emerging evidence suggests that cancer progression is often associated with the acquisition of Epithelial-to- Mesenchymal Transition (EMT) phenotype that is reminiscent of "Cancer Stem-like Cells (CSCs)", which is partly responsible for the ability of pancreatic cancer (PC) cells to acquire aggressiveness, contributing to tumor metastasis. Our published data showed decreased expression of miR-200 in gemcitabine resistant EMT- type cells, resulting in the up-regulation of ZEB1 and thereby down-regulation of E-cadherin, and also showed increased expression of miR-21, resulting in the inactivation of PTEN expression. We also found significantly higher levels of miR-21 in the plasma of PC patients compared to normal volunteers, which was correlated with worsened survival. Based on these results, we reasoned that finding a novel non-toxic avenue by which miR- 200 could be up-regulated and miR-21 could be down-regulated would be a novel approach for the prevention of tumor progression. To that end, we have published, for the first time, that a synthetic analog of a non-toxic natural agent curcumin, named CDF is superior in its target tissue (pancreas) bioavailability without any adverse side effects, and the CDF was very effective in the elimination of EMT phenotypic cells, which was in part due to up-regulation of miR-200 and down-regulation of miR-21, resulting in the down-regulation of ZEB1, and increased expression of E-cadherin and PTEN. Therefore, it appears that we found a novel approach by which "conditioning" of the biological milieu of drug-resistant EMT-type cells could be achieved toward effective elimination of EMT-type cells or CSCs, which could be useful for the prevention of tumor progression by eliminating the "root" cause of tumor recurrence. Based on our preliminary results, we hypothesize that the activation of miR-21 is critical during the acquisition of EMT phenotype in gemcitabine-resistant (GR) PC cells, and these cells could be eliminated by CDF alone or in combination with conventional therapeutics. We will test our hypothesis to gain mechanistic insight on the role of miR-21 and PTEN during the acquisition of EMT phenotype in GR cells, and investigate the biological consequence of these cells by manipulating the expression of miR-21 (Aim-1). We will also investigate how CDF could down-regulate miR- 21 and up-regulate the expression of its targets. This may lead to the "conditioning" of the biological milieu of PC cells, resulting in sensitization of cells to conventional agents (Aim-2; in vitro studies). Finally, we will determine whether CDF could cause increased anti-tumor activity when combined with conventional therapeutics in vivo using xenograft and K-ras transgenic animal models compared to CDF alone (Aim-3). The results of our studies will provide mechanistic insight as to the role of miR-21 in drug-resistant EMT-type cells (CSCs), and will also provide pre-clinical data in support of the role of CDF for the prevention of tumor progression and/or treatment of PC. Therefore, our results will have significantly high impact toward preventing tumor recurrence, which will lead to achieve better survival outcome of patients diagnosed with PC.

描述（由申请人提供）：新兴证据表明，癌症的进展通常与获得上皮到间质转变（EMT）表型有关，后者让人联想到“癌症干细胞（CSC）”，这部分负责胰腺癌（PC）细胞的能力（PC）攻击侵袭，贡献了Metors nemors nemors sastass，贡献了侵略性。我们已发表的数据显示，在吉西他滨抗EMT型细胞中miR-200的表达降低，导致Zeb1的上调，从而下调E-钙粘蛋白，并且还显示了miR-21的表达增加，导致PTEN表达失活。我们还发现，与正常志愿者相比，PC患者血浆中的miR-21水平明显更高，这与生存率恶化有关。基于这些结果，我们认为找到一种可以上调的新型无毒途径，而MiR-200可以下调，这将是一种预防肿瘤进展的新方法。 To that end, we have published, for the first time, that a synthetic analog of a non-toxic natural agent curcumin, named CDF is superior in its target tissue (pancreas) bioavailability without any adverse side effects, and the CDF was very effective in the elimination of EMT phenotypic cells, which was in part due to up-regulation of miR-200 and down-regulation of miR-21, resulting in the down-regulation of Zeb1，以及E-钙粘蛋白和PTEN的表达增加。因此，似乎我们发现了一种新颖的方法，可以通过这种方法来实现耐药EMT型细胞的“调节”，以有效消除EMT型细胞或CSC，这可能通过消除肿瘤复发的“根部”原因来预防肿瘤进展。基于我们的初步结果，我们假设MiR-21的激活在吉西他滨耐药（GR）PC细胞中获得EMT表型期间至关重要，并且可以单独或与常规治疗学结合使用CDF消除这些细胞。我们将测试我们的假设，以获取对MiR-21和PTEN在GR细胞中获得EMT表型过程中的作用的机理见解，并通过操纵miR-21的表达来研究这些细胞的生物学后果（AIM-1）。我们还将研究CDF如何下调miR-21并上调其靶标的表达。这可能导致PC细胞生物环境的“调节”，从而导致细胞对常规剂的敏感性（AIM-2；体外研究）。最后，我们将确定与仅CDF相比，使用异种移植物和K-Ras转基因动物模型与常规体内疗法结合时，CDF是否会引起抗肿瘤活性的增加（AIM-3）。我们的研究结果将提供有关miR-21在耐药EMT型细胞（CSC）中的作用的机理见解，并将提供临床前数据，以支持CDF在预防肿瘤进展和/或PC处理中的作用。因此，我们的结果将对预防肿瘤复发产生显着影响，这将导致诊断为PC的患者获得更好的生存结果。