The role of entosis in human cancers

嵌入在人类癌症中的作用

基本信息

批准号：
8021462
负责人：
Michael H. Overholtzer
金额：
$ 37.1万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021462
关键词：
Actins Adherens Junction Adhesions Affect Agar Anchorage-Independent Growth Aneuploid Cells Aneuploidy Apoptosis Autophagocytosis Biological Biological Assay Blocking Antibodies Breast Cadherins Cell Adhesion Cell Adhesion Molecules Cell Death Cell-Cell Adhesion Cells Cellular Structures Colon Complex Cytokinesis Cytoskeleton Deltastab Electron Microscopy Epithelial Cells Extracellular Matrix Failure Frequencies Generations Growth Human Human Cell Line Image In Vitro Intercellular Junctions Lung Malignant Neoplasms Mammary Neoplasms Mediating Mediator of activation protein Molecular Noninfiltrating Intraductal Carcinoma Pathway interactions Physiological Ploidies Population Process Production Proteins Reagent Recruitment Activity Reporting Resistance Role Small Interfering RNA Staging Tight Junctions Time Tumor Cell Line Tumor Suppression Tumorigenicity Vacuole Work cancer therapy design epithelial to mesenchymal transition in vivo inhibitor/antagonist insight neoplastic cell prevent programs research study restoration rho GTP-Binding Proteins small hairpin RNA tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Recently a mechanism was described whereby human cells internalize into neighboring cells, called entosis. Entosis underlies the formation of 'cell-in-cell' structures, where viable cells are engulfed inside of others. These unusual cell structures have been reported in human tumors for decades, but their physiological role remains unknown. Entosis is induced by detachment of cells from extracellular matrix in vitro, and is prevalent in anchorage-independent growth assays in soft agar. In breast tumors, cell-in- cell structures are found in early-stage (DCIS) tumors, and also in late stage invasive tumors, in matrix-deprived regions, suggesting that this process could affect the formation or metastatic spread of cancers. Although cells internalized by entosis are initially viable, most eventually undergo cell death, suggesting that entosis could be a mechanism of tumor suppression. Cell death occurs by a nonapoptotic mechanism that can eliminate cells which are resistant to apoptosis. Entosis may therefore act as a backup or cooperative tumor suppressive mechanism to apoptosis to prevent transformed growth. The identification of this cellular program, whose evidence in vivo far predates the in vitro mechanism, was made possible only by real-time imaging of a classical assay of tumorigenicity, where the basic cellular programs that control the ability to grow are not defined. This proposal describes plans to examine tumorigenic transformation by real-time imaging, to elucidate the molecular mechanisms of entosis, and to examine the role of this process in human cancers. PUBLIC HEALTH RELEVANCE: As cell-in-cell structures are reported in a variety of cancers, such as breast, colon, and lung, the elucidation of the entosis mechanism has the potential to uncover a previously overlooked basic cell biological aspect of some of the most common, and deadliest human cancers. Because the design of new cancer therapies is often tied to mechanistic information about how cell death works in tumor cells, understanding entosis could provide insight into new strategies for how these cancers might be treated.

描述（由申请人提供）：最近描述了一种机制，其中人类细胞内部化为邻近细胞，称为诱惑。诱惑是“细胞内”结构形成的基础，在其他人内部吞没了活的细胞。这些不寻常的细胞结构已经在人类肿瘤中报道了数十年，但它们的生理作用仍然未知。诱因是通过体外细胞外基质脱离细胞的诱导，并且在软琼脂中独立于锚定的生长测定中普遍存在。在乳腺肿瘤中，在早期（DCIS）肿瘤中发现细胞结构，以及在抑制基质的侵入性区域的后期浸润性肿瘤中，表明此过程可能会影响癌症的形成或转移性传播。尽管最初是通过诱惑而内化的细胞是可行的，但大多数人最终会经历细胞死亡，这表明诱惑可能是抑制肿瘤的机制。细胞死亡是通过一种可以消除对凋亡抗性的细胞的非凋亡机制发生的。因此，诱惑可以充当凋亡的备用或合作肿瘤抑制机制，以防止转化的生长。该细胞程序的鉴定，其在体内的证据远早于体外机制，只有通过对经典的肿瘤性测定法进行实时成像才能实现，在该测定中，控制增长能力的基本细胞程序未定义。该提案描述了通过实时成像，阐明诱惑的分子机制并检查该过程在人类癌症中的作用的计划。公共卫生相关性：随着细胞中的细胞结构在乳腺癌，结肠和肺部等各种癌症中报道，阐明这种诱惑机制的可能会揭示出以前最常见，最致命的人类癌症的先前被忽视的基本细胞生物学方面。由于新癌症疗法的设计通常与有关细胞死亡如何在肿瘤细胞中起作用的机械信息有关，因此了解诱惑可以洞悉如何治疗这些癌症。