Radiation survivors: understanding and exploiting the phenotype following fractionated radiation therapy.
Radiation survivors: understanding and exploiting the phenotype following fractionated radiation therapy.
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DOI：
10.1158/1541-7786.mcr-12-0492
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Coleman CN
中科院分区：
文献类型：
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作者：
Makinde AY;John-Aryankalayil M;Palayoor ST;Cerna D;Coleman CN
放射肿瘤学模式，如强度调节和图像引导放射治疗，可以减少对正常组织的高剂量，并向肿瘤提供异质性剂量，聚焦于肿瘤持续风险最高的区域。临床放射肿瘤学产生的日剂量范围为1至20 Gy，组织每天暴露于30个或更多的部分。假设在分次放射治疗中存活的细胞与未治疗的细胞具有明显不同的表型，这可能用于分子治疗或免疫治疗的靶向，我们研究了三种前列腺癌细胞系（PC3， DU145和LNCaP）和正常内皮细胞，以了解0.5、1和/或2 Gy分次放射（MF）至10 Gy总剂量以及5和10 Gy单剂量（SD）的不同生物学效应。分析mRNA、miRNA和磷酸化蛋白质组的变化。在中频辐射暴露中观察到显著差异，包括0.5戈瑞的中频辐射，产生少量细胞杀伤。正如预期的那样，p53功能在反应中发挥了主要作用。被MF修饰的途径包括免疫应答、DNA损伤、细胞周期阻滞、TGF-β、存活和凋亡信号转导。辐射诱导的应激反应将为利用放射治疗的效果提供一个独特的平台，作为与分子靶向或免疫定向治疗相结合的癌症治疗的“聚焦生物学”。考虑到更多的正常组织被治疗，尽管使用这些新技术的剂量较低，正常组织的反应也可能影响长期治疗结果。
Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing that cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145 and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multi-fraction (MF) radiation of 0.5, 1 and/or 2 Gy fraction to 10 Gy total dose, and a single dose (SD) of 5 and 10 Gy. The resulting changes in mRNA, miRNA and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell cycle arrest, TGF-β, survival and apoptotic signal transduction. The radiation-induced stress response will set-forth a unique platform for exploiting the effects of radiation therapy as “focused biology” for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome.