Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer.
Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer.
复制标题
DOI：
10.1158/1541-7786.mcr-18-0232
复制
发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Coleman CN
中科院分区：
文献类型：
--
作者：
Eke I;Makinde AY;Aryankalayil MJ;Reedy JL;Citrin DE;Chopra S;Ahmed MM;Coleman CN
肿瘤细胞对放射治疗的适应性导致可由分子靶向制剂和免疫疗法操作的变化。这份报告表明，辐射诱导的整合素表达变化可以在两个月后进行靶向治疗。整合素是一种跨膜细胞黏附分子，对癌细胞的存活和增殖至关重要。为了分析辐射对整合蛋白表达的短期和长期影响，将前列腺癌细胞(DU145、PC3和LNCaP)培养在3D细胞外基质中，并进行单次照射(2-10Gy射线)或分次照射(2-10Gy1Gy2-10次)。进行了全人类基因组芯片、免疫印迹、免疫沉淀分析和整合素的免疫荧光染色。结果在前列腺癌异种移植模型系统中得到了证实。有趣的是，β-1和β-4整合素(ITGB1和ITGB4)在体外和体内照射后上调。这种过度表达持续了两个多月，并呈剂量依赖关系。此外，经抑制性抗体处理后，辐射诱导的β1和β4整合素表达上调导致肿瘤细胞死亡显著增加。综上所述，这些发现表明，肿瘤对辐射的长期适应可以导致存活的癌细胞对分子靶向治疗的敏感性增加，这是由于辐射诱导的靶向过度表达。
Adaptation of tumor cells to radiation therapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted two months later. Integrins are transmembrane cell adhesion molecules which are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2–10 Gy) or a multi-fractionated regimen (2–10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (ITGB1 and ITGB4) were upregulated after radiation in vitro and in vivo. This overexpression lasted for more than two months and was dose-dependent. Moreover, radiation-induced upregulation of β1 and β4 integrin resulted in significantly increased tumor cell death after treatment with inhibitory antibodies. Combined, these findings indicate that long-term tumor adaptation to radiation can result in an increased susceptibility of surviving cancer cells to molecular targeted therapy due to a radiation-induced overexpression of the target.