Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.
Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.
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CXCR4的抑制增强了放射疗法在转移性前列腺癌模型中的疗效。
作者：
我们检测了SDF1CXCR4及其同源受体CXCR4在人前列腺癌(PCa)病变中的表达，以及在小鼠原位前列腺癌模型中CXCR4单独抑制和联合单剂量照射的影响。SDF1α和CXCR4在原发和骨转移癌组织中均有高表达。抑制PCa细胞中CXCR4的活性可抑制SDF1α诱导的侵袭，但不能使其对辐射增敏。在原位原发和骨转移PCA模型中，仅用CXCR4拮抗剂AMD3100治疗无效，但与放射治疗一起使用时，它显著抑制转移瘤的生长。AMD3100的作用机制包括骨转移性前列腺癌血管的正常化。这些结果支持在转移性前列腺癌患者中检测SDF1CXCR4抑制剂和放射治疗。放射治疗(RT)是晚期前列腺癌(PCA)患者的标准治疗方法。以往的临床前研究表明，SDF1α/CXCR4轴可介导PCa转移(最常见的是骨转移)和肿瘤对RT的抵抗。我们发现SDF1α及其受体CXCR4在原发和转移性前列腺癌组织中都有高水平的表达。使用PCA细胞进行的体外分析显示，CXCR4在细胞侵袭中发挥了重要作用，但不是辐射耐受性。AMD3100对CXCR4的药理抑制作用在原位原发和骨转移的PCa模型中无效。然而，当AMD3100与RT联合使用时，在两种模型中，AMD3100都增强了局部单次剂量RT(12GY)的效果。此外，抑制CXCR4也减少了原发PCa的淋巴转移。值得注意的是，抑制CXCR4促进了骨转移性PCA血管的正常化，并减少了组织缺氧。结论：SDF1α/CXCR4轴是放疗治疗转移性前列腺癌的潜在靶点。
We examined the expression of SDF1α and its cognate receptor CXCR4 in human prostate cancer (PCa) lesions and the impact of CXCR4 inhibition alone and in combination with single-dose irradiation in orthotopic PCa models in mice. Both SDF1α and CXCR4 were highly expressed in primary and bone metastatic human PCa samples. Inhibiting CXCR4 activity in PCa cells abrogated SDF1α-induced invasion but did not sensitize them to irradiation in vitro. In orthotopic primary and bone metastatic PCa models, treatment with the CXCR4 antagonist AMD3100 alone was ineffective, but when added to radiotherapy, it significantly inhibited metastatic tumor growth. The mechanisms of AMD3100 included normalization of bone metastatic PCa vasculature. These results support testing SDF1α/CXCR4 inhibitors with radiotherapy in metastatic PCa patients. Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.
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