Osteopontin and microenvironment of initiated cells

骨桥蛋白和启动细胞的微环境

基本信息

批准号：
7735525
负责人：
PI-LING CHANG
金额：
$ 30.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7735525
关键词：
Acetates Adhesiveness Adhesives Affect Anoikis Apoptosis Basal Cell Benign Binding Biological Models Calcium Binding Carcinogens Cell Line Cell Proliferation Cell Surface Receptors Cell surface Cells Chemopreventive Agent Chemotaxis Chronic Data Development Diagnosis Disease Drug resistance Elements Epidermis Epigenetic Process Event Exhibits Exposure to Funding Future Genetic Transcription Glycoproteins Goals Head and Neck Squamous Cell Carcinoma In Vitro Incidence Inhibition of Apoptosis Integrins Intrinsic factor Keratin Knockout Mice Knowledge Life Light Malignant Neoplasms Measures Mediating Modeling Molecular Mus Mutation NF-kappa B Neoplasm Metastasis Nitric Oxide Nitric Oxide Synthase Papilloma Patients Play Premalignant Cell Preventive Process Production Proliferating Property Protein Isoforms Proteins Proto-Oncogenes Role Signal Transduction Signaling Molecule Skin Carcinogenesis Squamous cell carcinoma Staging System Testing Time Transgenic Mice Tumor Promoters Tumor Promotion Tumor Suppressor Genes United States National Institutes of Health Wild Type Mouse autocrine cancer cell carcinogenesis cell transformation design dimethylbenzanthracene improved in vivo keratinocyte mouse model neoplastic cell osteopontin prevent tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

In contrast to the well studied role of intrinsic factors in tumorigenesis, knowledge regarding the mechanism(s) whereby extrinsic factors, such as the stromal/matrix microenvironment, influence an initiated cell with permanent genetic alterations to transform into a tumor is largely unknown. Identifying these key cell signaling events that regulate initiated cells during the tumor promotion stage is an attractive target for designing preventive agents, because initiated cells unlike malignant cells can remain dormant for an extended period of time and are genetically stable, resulting in decreased drug resistance compared with genetically unstable transformed cells. Our long term goals are to define the rate-limiting factors in the matrix microenvironment that affect the survival and/or proliferation of initiated cells. We have identified one of these critical stromal/matrix elements to be osteopontin (OPN), which is a key factor in regulating the survival of initiated cells. We hypothesize that OPN, which is induced during initiation and further induced during tumor promotion, functions in tumorigenesis by preventing apoptosis of transforming keratinocytes (KC) directly through cell surface receptor interaction and/or indirectly by inhibiting the autocrine production of nitric oxide (NO) mediated through suppression of nitric oxide synthase(NOS) production. We define transforming KCs as initiated KCs, which subsequently undergo transformation, and development into papillomas. Our in vivo endpoint of this transforming process is the papilloma, which is readily measured. Specifically, within the two years of funding, we will perform in vitro studies and short-term in vivo studies to 1) define whether OPN functions in the early tumor promotion stages by increasing the proliferation of or by preventing the apoptosis of transforming KC, and 2) elucidate whether OPN-mediated signaling induced by tumor promoters decreases NOS levels and hence NO production. These proposed in vivo and in vitro studies will shed light on the molecular mechanism(s) by which a matricellular protein enhances the survival of transforming cells during early tumor promotion.

与内在因素在肿瘤发生中的作用的充分研究相反，关于外在因素（例如基质/基质微环境）影响具有永久性遗传改变的起始细胞转化为肿瘤的机制的知识在很大程度上是未知的。识别这些在肿瘤促进阶段调节启动细胞的关键细胞信号转导事件是设计预防药物的一个有吸引力的目标，因为与恶性细胞不同，启动细胞可以长时间保持休眠状态并且遗传稳定，从而导致与恶性细胞相比耐药性降低。具有遗传不稳定的转化细胞。我们的长期目标是确定基质微环境中影响起始细胞存活和/或增殖的限速因素。我们已经确定这些关键基质/基质元素之一是骨桥蛋白（OPN），它是调节起始细胞存活的关键因素。我们假设 OPN 在肿瘤发生过程中被诱导，并在肿瘤促进过程中进一步诱导，通过细胞表面受体相互作用直接防止转化角质形成细胞 (KC) 凋亡和/或通过抑制一氧化氮 (NO) 自分泌产生间接防止转化角质形成细胞 (KC) 凋亡，从而在肿瘤发生中发挥作用。通过抑制一氧化氮合酶（NOS）的产生来介导。我们将转化型 KC 定义为起始 KC，随后发生转化并发展为乳头状瘤。我们这个转化过程的体内终点是乳头状瘤，它很容易测量。具体来说，在资助的两年内，我们将进行体外研究和短期体内研究，以1）确定OPN是否通过增加转化KC的增殖或阻止其凋亡来在早期肿瘤促进阶段发挥作用，以及2) 阐明肿瘤启动子诱导的 OPN 介导的信号传导是否会降低 NOS 水平，从而降低 NO 的产生。这些体内和体外研究将揭示基质细胞蛋白在早期肿瘤促进过程中增强转化细胞存活的分子机制。