The role of entosis in human cancers

描述（由申请人提供）：最近描述了一种机制，其中人类细胞内化到邻近细胞中，称为内吞。内吞是“细胞中细胞”结构形成的基础，在这种结构中，活细胞被吞噬在其他细胞内部。这些不寻常的细胞结构已经在人类肿瘤中报道了几十年，但它们的生理作用仍然未知。内吞是由体外细胞从细胞外基质中脱离诱导的，并且在软琼脂中的锚定非依赖性生长测定中是普遍的。在乳腺肿瘤中，在早期（DCIS）肿瘤中发现了细胞中细胞结构，并且在晚期侵袭性肿瘤中，在基质剥夺区域中也发现了细胞中细胞结构，这表明该过程可能影响癌症的形成或转移扩散。虽然通过内吞内化的细胞最初是存活的，但大多数最终经历细胞死亡，这表明内吞可能是肿瘤抑制的机制。细胞死亡通过非凋亡机制发生，该机制可以消除对凋亡具有抗性的细胞。因此，内吞可以作为细胞凋亡的后备或协同肿瘤抑制机制，以防止转化生长。这种细胞程序的鉴定，其在体内的证据远远早于体外机制，只有通过实时成像的一个经典的致瘤性测定，其中控制生长能力的基本细胞程序没有定义。该提案描述了通过实时成像检查致瘤性转化的计划，以阐明entosis的分子机制，并检查该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.