Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth.
Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth.
复制标题
DOI：
10.1158/0008-5472.can-09-2747
复制
发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Koong AC
中科院分区：
文献类型：
--
作者：
Spiotto MT;Banh A;Papandreou I;Cao H;Galvez MG;Gurtner GC;Denko NC;Le QT;Koong AC
癌细胞存在于恶劣的微环境中，这种微环境受各种因素的支配，包括缺氧和营养缺乏。这些微环境应激源激活了影响癌细胞存活的信号通路。虽然其他人之前已经测量了肿瘤中的微环境应激源，但仍然很难在原发肿瘤中检测到这些下游信号通路的实时激活。在这里，我们开发了表达X-box结合蛋白1(XBP1)-荧光素酶结构的转基因小鼠，该结构作为内质网(ER)应激的报告基因和肿瘤微环境的下游反应。我们发现发生在这些小鼠身上的原发乳腺肿瘤在体内具有荧光素酶活性。发生在同一小鼠的多个肿瘤具有不同的XBP1-荧光素酶特征，反映了较高或较低水平的内质网应激。未检测到XBP1-荧光素酶活性的原发肿瘤在移植后获得了生物发光信号，表明XBP1-荧光素酶活性水平反映了单个原发肿瘤独特的微环境。此外，内质网应激的变化反映了肿瘤之间代谢和缺氧的差异。最后，XBP1-荧光素酶活性与肿瘤生长速度相关。因此，我们可以在原发肿瘤中可视化不同的信号通路，这些信号通路反映了独特的肿瘤微环境，不同的代谢特征，并可以预测肿瘤的生长。
Cancer cells exist in harsh microenvironments which are governed by various factors including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect a cancer cell’s survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real time activation of these downstream signaling pathways in primary tumors. Here, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. We find that primary mammary tumors arising in these mice possessed luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Primary tumors with undetectable XBP1-luciferase activity gained bioluminescent signal after transplantation indicating that the level of XBP1-luciferase activity reflected unique microenvironments of individual primary tumors. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Thus, we can visualize distinct signaling pathways in primary tumors that reflect unique tumor microenvironments, distinct metabolic signatures and may predict for tumor growth.