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LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy.
Oncogene ( IF 6.9 ) Pub Date : 2018-Sep-01 , DOI: 10.1038/s41388-018-0320-2
Leonie Rossow , Simona Veitl , Sandra Vorlová , Jacqueline K. Wax , Anja E. Kuhn , Verena Maltzahn , Berin Upcin , Franziska Karl , Helene Hoffmann , Sabine Gätzner , Matthias Kallius , Rajender Nandigama , Daniela Scheld , Ster Irmak , Sabine Herterich , Alma Zernecke , Süleyman Ergün , Erik Henke

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.

中文翻译:

LOX催化的胶原蛋白稳定是化学内在抗性的近端原因。

改变肿瘤ECM以改善药物反应的潜力仍未开发。为了确定修饰ECM的目标,以改善药物反应和克服耐药性,我们分析了来自治疗前患者队列的表达数据集。交叉评估确定了化学抗性肿瘤的一个子集,其特征是胶原蛋白和胶原稳定酶的表达增加。我们证明强大的胶原蛋白表达和稳定作用会引发自我传播的缺氧,恶性信号传导和异常血管生成的恶性循环,可以通过适当的辅助干预手段来打破这种循环:通过抑制赖氨酰氧化酶来干扰胶原蛋白的稳定作用可显着增强对化疗的反应各种肿瘤模型,甚至在转移性疾病中也是如此。取决于肿瘤类型,本身抑制胶原蛋白稳定化可以减少或增强肿瘤的生长。这种行为的机理基础是一方面单个肿瘤依赖于营养供应,另一方面依赖于FAK信号传导的高组织刚度。
更新日期:2018-05-21
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