Crosstalk between Epithelial and Mesenchymal Tissues in Tumorigenesis and Imaginal Disc Development
Crosstalk between Epithelial and Mesenchymal Tissues in Tumorigenesis and Imaginal Disc Development
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DOI：
10.1016/j.cub.2014.05.043
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发表时间：
2014-07-07
期刊：
影响因子：
9.2
通讯作者：
Cohen, Stephen M.
中科院分区：
文献类型：
--
作者：
Herranz, Hector;Weng, Ruifen;Cohen, Stephen M.
背景：癌症在一个复杂的突变环境中发展。基因异常的癌细胞与正常的造口细胞的相互作用可以改变局部微环境，促进某些肿瘤类型的疾病进展。肿瘤发生的遗传模型为探索癌症驱动突变的组合如何赋予肿瘤不同的特性提供了机会。以前的egfr驱动的果蝇癌症模型主要集中在上皮瘤变上。结果：在这里，我们报告了egfr驱动的果蝇肿瘤发生的遗传模型，其中肿瘤转化依赖于上皮细胞和间充质细胞之间的相互作用。我们提供的证据表明，分泌的蛋白聚糖Perlecan可以作为一种环境依赖的癌基因，与EGFR合作，促进肿瘤的发生。在表达egfr的上皮细胞中，Perlecan的共表达增强了来自上皮细胞的内源性Wg/Wnt和Dpp/BMP信号，以支持间质室的扩张。上皮细胞需要Wg活性，而间质细胞需要Dpp活性。这种基因正常的间充质间室是支持基因修饰上皮细胞群生长和肿瘤转化所必需的。结论：我们报道了肿瘤形成的遗传模型，该模型依赖于基因修饰的上皮细胞群和正常宿主间充质细胞之间的串扰。在这个模型中，肿瘤的发生采用了一种调节机制，这种机制通常在发育过程中参与控制想象椎间盘的生长。
Background: Cancers develop in a complex mutational landscape. Interaction of genetically abnormal cancer cells with normal stomal cells can modify the local microenvironment to promote disease progression for some tumor types. Genetic models of tumorigenesis provide the opportunity to explore how combinations of cancer driver mutations confer distinct properties on tumors. Previous Drosophila models of EGFR-driven cancer have focused on epithelial neoplasia.Results: Here, we report a Drosophila genetic model of EGFR-driven tumorigenesis in which the neoplastic transformation depends on interaction between epithelial and mesenchymal cells. We provide evidence that the secreted proteoglycan Perlecan can act as a context-dependent oncogene cooperating with EGFR to promote tumorigenesis. Coexpression of Perlecan in the EGFR-expressing epithelial cells potentiates endogenous Wg/Wnt and Dpp/BMP signals from the epithelial cells to support expansion of a mesenchynnal compartment. Wg activity is required in the epithelial compartment, whereas Dpp activity is required in the mesenchymal compartment. This genetically normal mesenchymal compartment is required to support growth and neoplastic transformation of the genetically modified epithelial population.Conclusions: We report a genetic model of tumor formation that depends on crosstalk between a genetically modified epithelial cell population and normal host mesenchymal cells. Tumorigenesis in this model co-opts a regulatory mechanism that is normally involved in controlling growth of the imaginal disc during development.