The role of entosis in human cancers

描述(申请人提供)：最近描述了一种人类细胞内化到相邻细胞的机制，称为齿状突。Entosis是形成“细胞中的细胞”结构的基础，在这种结构中，有生命的细胞被吞噬在其他细胞中。这些不寻常的细胞结构在人类肿瘤中已经被报道了几十年，但它们的生理作用仍然不清楚。Entosis是由细胞在体外从细胞外基质中分离而引起的，在软琼脂中普遍存在于非锚定生长试验中。在乳腺肿瘤中，细胞内结构存在于早期(DCIS)肿瘤和晚期侵袭性肿瘤中，位于基质剥夺的区域，这表明这一过程可能影响癌症的形成或转移。虽然内在化的细胞最初是存活的，但大多数最终都会经历细胞死亡，这表明内在化可能是肿瘤抑制的一种机制。细胞死亡是通过一种非凋亡性机制发生的，这种机制可以消除抵抗细胞凋亡的细胞。因此，Entosis可能作为一种备份或协同的肿瘤抑制机制来抑制细胞凋亡，以防止转化生长。对这种细胞程序的鉴定，其体内证据远远早于体外机制，只有通过对经典的致瘤性分析进行实时成像才能实现，在这种方法中，控制生长能力的基本细胞程序尚未定义。这项建议描述了通过实时成像检查致瘤转化的计划，以阐明齿状瘤的分子机制，并检查这一过程在人类癌症中的作用。

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.