Discovering Microenvironments Promoting Pathological EMT using Array Technology

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，肺癌占癌症相关死亡的29%，超过乳腺癌，结肠癌和前列腺癌的总和。目前的常规疗法-手术、化疗、放疗等对于许多形式的肺癌远不能治愈。转移，肿瘤细胞扩散到远处部位，是原发性肿瘤治疗后的常见结果，并且是癌症患者死亡的主要原因。导致转移的机制和时间进展仍然不清楚。最近的研究已经将癌症转移与上皮-间质转化（EMT）的不适当再激活联系起来。在此过程中，不动的极化上皮细胞转化为高度运动的非极化上皮细胞， 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）、白细胞介素-1（IL-1）、肝细胞生长因子（HGF）和Wnt配体。在各种病理性EMT系统中的大量研究提供了令人信服的证据，多功能细胞因子TGF-2信号转导是EMT的主要诱导剂。除了这些已经表明在EMT诱导中的因素之外，肿瘤微环境如细胞外基质（ECM）也可以对EMT施加强有力的影响。尽管经过几十年的研究，EMT和ECM - EMT相互作用在肺癌发生中的作用仍不清楚.迄今为止，研究人员仍在努力建立适当的体外模型，以模拟驱动EMT过程的临床相关微环境的特性。MicroStem公司开发了一种新的平台技术，可以在功能化载玻片上单独或组合筛选数千种ECMPs，生长因子和信号分子。可以监测和量化这些条件下的细胞行为。MicroStem将利用这种专门的细胞阵列筛选系统来阐明驱动肺癌细胞EMT过程的生理相关微环境。我们独特的MicroMatrixTM阵列技术将作为一个新的平台来了解肿瘤细胞与其微环境（细胞-细胞，细胞-基质）之间的相互作用。本研究的结果将进一步加深对肺癌侵袭和转移的自然过程的基本认识，从而为发现现有化疗的更好疗效奠定基础，并为新型治疗药物开辟新的前沿。 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生理相关的微环境，包括细胞外基质蛋白，生长因子和促进肺癌细胞上皮间质转化（EMT）的信号分子。我们独特的MicroMatrixTM阵列技术将为了解肿瘤细胞与其微环境（细胞-细胞，细胞-基质）之间的相互作用提供一个新的平台。本课题的研究结果将进一步加深我们对肺癌侵袭和转移的基本认识，为发现更好的化疗效果奠定基础，并为新型治疗药物开辟新的前沿。

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.