权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Engineered Microenvironments to model effect of size in tumor progression

工程微环境模拟肿瘤进展中大小的影响

基本信息

批准号：
8829249
负责人：
Shilpa Sant
金额：
$ 7.7万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829249
关键词：
Affect Apoptosis Apoptotic Area Basal Cell Basal Cell Cancer Basic Science Biological Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cell Communication Cell-Cell Adhesion Cells Clinical Clinical Research Coupled Data E-Cadherin Engineering Epithelial Epithelium Event Exhibits Extracellular Matrix Generations Growth Health Hormonal Hydrogels Hypoxia Immunohistochemistry Intercellular Fluid Kinetics Link MCF10A cells MCF7 cell Mesenchymal Metabolic stress Modeling Molecular Molecular Profiling Morbidity - disease rate N-Cadherin Necrosis Neoplasm Metastasis Nodal Nutritional Outcome Oxygen Pathway interactions Patients Pattern Phenotype Preclinical Drug Evaluation Proliferating RNA Interference Radial Regulation Role Signal Transduction Snails Spatial Distribution Stress Stromal Cells Technology Tumor Cell Invasion Up-Regulation Vimentin Work in vivo inhibitor/antagonist insight interstitial malignant breast neoplasm monolayer mortality neoplastic cell novel novel strategies pressure receptor slug small molecule three-dimensional modeling transcription factor tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to model the effect of tumor size and growth in promoting tumor progression. More specifically, the proposal aims to create a micro fabricated platform that will allow generation of uniform, size-controlled micro tumors in a high throughput manner and study size-dependent differences in tumor microenvironment, cell-cell interaction and transcription factors. Recently tumor microenvironment has been considered as an important player in tumorigenesis and progression leading to metastasis, a major cause of cancer-related mortality. Tumor microenvironment consists of tumor & stromal cells, extracellular matrix and non-cellular components that include hypoxia, interstitial pressure and metabolic stresses. Growing tumor exerts forces on the surrounding cells and epithelium creating radial and circumferential stress. Tumor growth also results in metabolic stress, hypoxia, necrosis, increased matrix stiffness and interstitial fluid pressure. Although tumor size has been considered as one of the important predictor of metastasis and patient survival, the mechanistic link between tumor size and the clinical outcome (metastasis, mortality) is not well understood. In breast cancer patients, this scenario is complicated by nodal and hormonal receptor status. This proposal aims 1) to develop three-dimensional (3D) micro fabricated platform to generate size-controlled micro tumors with controlled microenvironments using sub-type specific breast cancer cell lines and 2) to understand the effect of tumor size on microenvironment and delineate the mechanism by which tumor size promotes tumorigenesis and metastasis. Aim 1 will use micro fabrication technologies to pattern cells in non-adhesive hydrogel micro wells and generate size-controlled micro tumors of different sizes. Various sub-type specific cell lines (luminal, basal, triple negative etc.) will be used to investigate the size-dependent differences in their growth kinetics, hormonal status, cell-cell interaction and tumor microenvironment. In Aim 2, size-dependent transcriptional changes in micro tumors will be studied and this information will be used further to understand the mechanism behind tumor size-related tumor progression using RNA interference and small molecule inhibitors. The proposed approach is novel, easy and inexpensive and will allow fabricating 3D micro tumor models in a high throughput manner. Ability to control microenvironments in size-dependent manner will facilitate discovery of key signaling mechanisms involved in the regulation of morphological and transcriptional changes in tumor cells. This approach can potentially be used as a more relevant 3D drug screening platform to replace current 2D cell monolayers.

描述（由申请人提供）：本提案的目的是模拟肿瘤大小和生长在促进肿瘤进展中的作用。更具体地说，该提案旨在创建一个微型制造平台，该平台将允许以高通量的方式生成均匀的，尺寸控制的微型肿瘤，并研究肿瘤微环境，细胞-细胞相互作用和转录因子的尺寸依赖性差异。近年来，肿瘤微环境被认为是肿瘤发生、发展和转移的重要因素，是癌症相关死亡的主要原因。肿瘤微环境由肿瘤及间质细胞、细胞外基质及缺氧、间质压力、代谢应激等非细胞成分组成。生长中的肿瘤对周围细胞和上皮产生径向和周向应力。肿瘤生长还导致代谢应激、缺氧、坏死、基质硬度和间质液压力增加。尽管肿瘤大小被认为是转移和患者生存的重要预测因素之一，但肿瘤大小与临床结果（转移、死亡率）之间的机制联系尚不清楚。在乳腺癌患者中，这种情况因淋巴结和激素受体状态而变得复杂。本课题旨在：1)利用亚型特异性乳腺癌细胞系开发三维（3D）微制造平台，在可控微环境下生成尺寸可控的微肿瘤；2)了解肿瘤大小对微环境的影响，阐明肿瘤大小促进肿瘤发生和转移的机制。Aim 1将使用微制造技术在非黏附水凝胶微孔中对细胞进行图案化，并生成不同大小的尺寸可控的微肿瘤。将使用各种亚型特异性细胞系（管状，基底，三阴性等）来研究其生长动力学的大小依赖性差异。