Discovering Microenvironments Promoting Pathological EMT using Array Technology

使用阵列技术发现促进病理 EMT 的微环境

基本信息

批准号：
8252561
负责人：
Naira Serobyan
金额：
$ 15.55万
依托单位：
MICROSTEM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2013-12-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8252561
关键词：
A549 Antibodies Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Line Cell physiology Cells Cessation of life Collagen Colon Carcinoma Cultured Cells Cytoskeleton Distant E-Cadherin Epidermal Growth Factor Epithelial Epithelial Cells Evaluation Excision Extracellular Matrix Proteins Fibroblast Growth Factor 2 Fibroblasts Fibronectins Foundations Gene Expression Genes Glass Grant Growth Factor Hepatocyte Growth Factor Immunofluorescence Immunologic In Vitro Insulin-Like Growth Factor II Interleukin-1 Laminin Lead Libraries Ligands Link Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Mediator of activation protein Mesenchymal Monitor Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome Patients Pharmaceutical Preparations Phase Physiological Population Primary Neoplasm Printing Process Property Proteins Radiation therapy Research Research Personnel Role Screening for cancer Screening procedure Signal Transduction Signaling Molecule Site Slide Smooth Muscle Actin Staining Method System Technology Therapeutic Therapeutic Effect Transforming Growth Factors Tumor Cell Invasion Validation Vimentin Western Blotting base cancer cell cell behavior chemotherapy clinically relevant connective tissue growth factor conventional therapy cytokine drug discovery extracellular genetic analysis in vitro Model lung Carcinoma lung carcinogenesis malignant breast neoplasm mortality neoplastic cell novel novel therapeutics tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer remains a leading cause of cancer death worldwide. In the US, lung cancer is responsible for 29% of cancer-related death, more than breast, colon and prostate cancers combined. Current conventional therapy - surgery, chemotherapy, radiotherapy, etc. are far from being curative for many forms of lung cancer Metastasis, the spread of tumor cells to distant sites, is a common outcome after primary tumor treatment and is the primary cause of mortality in cancer patients. The mechanisms and the temporal progressions that lead to metastasis remain poorly defined. Recent studies have linked cancer metastasis to the improper reactivation of epithelial-mesenchymal transition (EMT). During this process, immotile polarized epithelial cells transform into highly motile apolar fibroblast-like cells. EMT induction has been linked to a number of extracellular mediators including transforming growth factor-2 (TGF-2), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), CTGF, insulin-like growth factor-2 (IGF-II), interleukin-1 (IL-1), hepatocyte growth factor (HGF), and Wnt ligands. Numerous studies in various pathological EMT systems provide convincing evidence that multifunctional cytokine TGF-2 signaling is a primary inducer of EMT. In addition to these factors that have been indicated in the EMT induction, tumor microenvironments such as extra cellular matrices (ECM) may also exert powerful influence on EMT. Despite of decade's research, the role of EMT and ECM - EMT interactions in the lung carcinogenesis remain unclear. To date, researchers are still struggling to establish proper in vitro models that mimic the properties of clinically relevant microenvironments that drive EMT process. MicroStem, Inc. has developed a novel platform technology which thousands of ECMPs, growth factors and signaling molecules can be screened individually and in combination on a functionalized glass slide. Cell behavior on these conditions can be monitored and quantified. MicroStem will utilize this specialized cell array screening system to elucidate the physiologically relevant microenvironments that drives the EMT process for lung cancer cells. Our unique MicroMatrixTM array technology will serve as a novel platform to understand the interaction between tumor cells and their microenvironment (cell-cell, cell-matrix). The results of this proposal will advance the basic understanding of the natural process for tumor invasion and metastasis in lung cancer; and therefore, laying out a foundation to discover better therapeutic effects of current chemotherapies and open a new front for novel therapeutic drugs. PUBLIC HEALTH RELEVANCE: MicroStem will utilize a specialized cell array screening system to identify physiologically relevant microenvironments consisting of extracellular matrix proteins, growth factors, and signaling molecules that promote epithelial mesenchymal transition (EMT) of lung cancer cells. Our unique MicroMatrixTM array technology will provide a novel platform to understand the interaction between tumor cells and their microenvironment (cell-cell, cell-matrix). The results of our proposal will advance our basic understanding on tumor invasion and metastasis in lung cancer; and therefore, laying out a foundation to discover a better therapeutic effect of current chemotherapy and open a new front for novel therapeutic drugs.

描述（由申请人提供）：肺癌仍然是全球癌症死亡的主要原因。在美国，肺癌造成了29％的与癌症相关的死亡，比乳腺癌，结肠和前列腺癌的合并更多。当前的常规疗法 - 手术，化学疗法，放疗等对于多种形式的肺癌转移而言，肿瘤细胞向远处部位的扩散远非治愈，这是原发性肿瘤治疗后的一个常见结果，并且是癌症患者死亡率的主要原因。导致转移的机制和时间进程的定义仍然很差。最近的研究将癌症转移与上皮 - 间质转变（EMT）的重新激活联系起来。在此过程中，Immotile极化上皮细胞转化为高度动动的Alolar 成纤维细胞样细胞。 EMT诱导与许多细胞外介质有关，包括转化生长因子-2（TGF-2），成纤维细胞生长因子2（FGF-2），表皮生长因子（EGF），CTGF，胰岛素样生长因子2（IGF-II），IGF-II），Illukin-1（IL-1）（IL-1）（IL-1），HEPATOCYTE，HGF（HGF），HGF（HGF），HGF（HGF），HGF。在各种病理EMT系统中的大量研究提供了令人信服的证据，表明多功能细胞因子TGF-2信号传导是EMT的主要诱导剂。除了在EMT诱导中指出的这些因素外，肿瘤微环境（例如额外的细胞基质（ECM））也可能对EMT产生强大的影响。尽管有十年的研究，但EMT和ECM -EMT相互作用在肺癌发生中的作用尚不清楚。迄今为止，研究人员仍在努力建立适当的体外模型，以模仿驱动EMT过程的临床相关微环境的特性。 Microstem，Inc。开发了一种新型的平台技术，可以单独筛选成千上万的ECMP，生长因子和信号分子，并在功能化的载玻片上组合进行筛选。可以监视和量化这些条件的细胞行为。 Microstem将利用这种专业的细胞阵列筛查系统来阐明驱动肺癌细胞EMT过程的生理相关的微环境。我们独特的MicromomomatrixTM阵列技术将成为一个新的平台，以了解肿瘤细胞与其微环境之间的相互作用（细胞 - 细胞，细胞矩阵）。该提案的结果将提高人们对肺癌肿瘤侵袭和转移自然过程的基本理解。因此，奠定了基础，以发现当前化学疗法的更好的治疗作用，并为新型治疗药物打开新的方面。公共卫生相关性：MicroStem将利用专门的细胞阵列筛选系统来识别由细胞外基质蛋白，生长因子和信号分子组成的生理相关的微环境，这些微环境促进肺癌细胞的上皮间质转化（EMT）。我们独特的MicromomomatrixTM阵列技术将为了解肿瘤细胞与其微环境之间的相互作用（细胞 - 细胞，细胞矩阵）提供新的平台。我们提案的结果将提高我们对肺癌肿瘤侵袭和转移的基本理解。因此，奠定了基础，以发现当前化疗的更好的治疗作用，并为新型治疗药物打开新的方面。