The Role of Metabolic Alterations in Anchorage-Independent Survival

代谢改变在锚地独立生存中的作用

基本信息

批准号：
7484234
负责人：
Zachary T. Schafer
金额：
$ 4.96万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7484234
关键词：
4 hydroxynonenal Acinar Cell Address Anoikis Apoptosis Apoptotic Autophagocytosis Basement membrane Behavior Biological Markers Biology Calcium-Binding Proteins Caspase Cell Death Cell Line Cell Survival Cell physiology Cells Cessation of life Collagen Commit Correlative Study Data Defect Digestion Duct (organ) structure Ductal Epithelial Cell Ectopic Expression Environment Epithelial Cells Experimental Models Extracellular Matrix Failure Family Gland Greek Growth Growth Factor Homelessness Inhibition of Apoptosis Integrins Island Laboratories Laminin Left Link Localized Mammary gland Mediating Membrane Proteins Metabolic Metabolism Metastasis Induction Modification Molecular Morphogenesis Mus NID gene Neoplasm Metastasis Normal Cell Nutrient Oncogenes Organelles Pathway interactions Personal Satisfaction Process Proteins Receptor Protein-Tyrosine Kinases Reporting Resistance Role Signal Pathway Signal Transduction Structure Tissues Tumor Cell Invasion Tumor Suppression Work adhesion receptor base cancer cell caspase-3 cell suicide immortalized cell in vivo killings matrigel neoplastic cell novel prevent psoriasin response tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The ability of cancer cells to survive in the absence of normal matrix is critical for tumor progression and metastasis. Normal (non-tumorigenic) cells that detach from the extracellular matrix (ECM) undergo caspase-dependent death (known as anoikis), a phenomenon that is frequently defective in cancer cells, thereby contributing to tumor progression. Interestingly, recent studies have revealed that inhibiting anoikis is not sufficient to allow for cell survival in abnormal matrix environments, as detached cells can die by an alternative death pathway. Preliminary work from our laboratory and correlative studies by other groups suggest that alterations in cellular metabolism may underlie the induction of this alternative death pathway in the absence of normal matrix and that oncogenes can modulate cellular metabolism to protect from non- apoptotic death. Thus, the modulation of cellular metabolism to induce non-apoptotic cell death in tumor cells may be a useful and important chemotherapeutic strategy. Therefore, we propose the following specific aims to address the role of metabolic changes in anchorage-independent survival. I. To analyze the basis for low metabolic activity in cells that have detached from the extracellular matrix. II. To understand how oncogenes rescue metabolic defects in cells that detach from the extracellular matrix. III. To characterize the importance of oncogene-mediated modifications in metabolism on tumor progression. Relevance One of the many things that differentiates cancer cells from normal cells is their inability to commit "cellular suicide" (known as apoptosis) when they migrate to an inappropriate environment. Recently, it has been discovered that cancer cells must also avoid an alternative form of cell death (distinct from apoptosis) in order to survive outside of their normal environment, and this death seems to be dependent on the way cancer cells process nutrients. Therefore, an understanding of how cancer cells process nutrients outside of their normal environment will provide valuable information that may identify novel ways to kill cancer cells that have inappropriately left their environments through the induction of this alternative form of cell death.

描述（由申请人提供）：在没有正常基质的情况下，癌细胞生存的能力对于肿瘤进展和转移至关重要。从细胞外基质（ECM）脱离的正常（非肿瘤）细胞经历了caspase依赖性死亡（称为Anoikis），这是一种经常在癌细胞中有缺陷的现象，从而有助于肿瘤进展。有趣的是，最近的研究表明，抑制Anoikis不足以允许在异常基质环境中存活，因为分离的细胞可能会因替代性死亡途径而死亡。来自我们实验室的初步工作和其他群体的相关研究表明，在没有正常基质的情况下，细胞代谢的改变可能是该替代死亡途径的诱导，并且致癌基因可以调节细胞代谢以防止非凋亡死亡。因此，细胞代谢诱导肿瘤细胞中非凋亡细胞死亡的调节可能是一种有用且重要的化学治疗策略。因此，我们提出了以下特定旨在解决代谢无关生存中代谢变化的作用。 I.分析从细胞外基质脱离的细胞中低代谢活性的基础。 ii。要了解癌基因如何挽救从细胞外基质脱离的细胞中的代谢缺陷。 iii。为了表征癌基因介导的修饰在代谢对肿瘤进展中的重要性。相关性将癌细胞与正常细胞区分开的众多因素之一是，当它们迁移到不适当的环境中时，它们无法实施“细胞自杀”（称为凋亡）。最近，已经发现，癌细胞还必须避免一种替代形式的细胞死亡形式（与凋亡不同），以便在其正常环境之外生存，并且这种死亡似乎取决于癌细胞处理营养的方式。因此，了解癌细胞如何在其正常环境之外处理养分的理解将提供有价值的信息，这些信息可能会通过诱导这种替代性细胞死亡形式来杀死不适当地离开其环境的癌细胞的新颖方法。