Elimination of Oncogenic Neighbors by JNK-Mediated Engulfment in Drosophila
Elimination of Oncogenic Neighbors by JNK-Mediated Engulfment in Drosophila
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DOI：
10.1016/j.devcel.2011.02.007
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发表时间：
2011-03-15
影响因子：
11.8
通讯作者：
Igaki, Tatsushi
中科院分区：
文献类型：
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作者：
Ohsawa, Shizue;Sugimura, Kaoru;Igaki, Tatsushi
上皮细胞群中新出现的致癌细胞必须面对宿主组织中的抗肿瘤选择压力。然而，周围正常组织对致癌转化细胞发挥抗肿瘤作用的机制知之甚少。在果蝇成虫上皮中，细胞克隆突变为进化上保守的肿瘤抑制基因，如scrib或dig失去其上皮完整性，并被野生型组织包围时从上皮中消除。在这里，我们表明，周围的正常细胞激活非凋亡JNK信号的致癌突变细胞的出现作出反应。这种JNK激活导致PVR（果蝇PDGF/VEGF受体）的上调。遗传学和时间推移成像分析显示，周围细胞中PVR的表达激活了埃尔莫/Mb介导的吞噬途径，从而通过吞噬消除致癌的邻居。我们的数据表明，JNK介导的细胞吞噬可能是一种进化上保守的内在肿瘤抑制机制，消除癌前细胞从上皮。
A newly emerged oncogenic cell in the epithelial population has to confront antitumor selective pressures in the host tissue. However, the mechanisms by which surrounding normal tissue exerts antitumor effects against oncogenically transformed cells are poorly understood. In Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressor genes such as scrib or dig lose their epithelial integrity and are eliminated from epithelia when surrounded by wild-type tissue. Here, we show that surrounding normal cells activate nonapoptotic JNK signaling in response to the emergence of oncogenic mutant cells. This JNK activation leads to upregulation of PVR, the Drosophila PDGF/VEGF receptor. Genetic and time-lapse imaging analyses reveal that PVR expression in surrounding cells activates the ELMO/Mbc-mediated phagocytic pathway, thereby eliminating oncogenic neighbors by engulfment. Our data indicate that JNK-mediated cell engulfment could be an evolutionarily conserved intrinsic tumor-suppression mechanism that eliminates premalignant cells from epithelia.