CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models
CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models
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DOI：
10.1002/pros.23007
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发表时间：
2015-09-01
期刊：
影响因子：
2.8
通讯作者：
Festuccia, Claudio
中科院分区：
文献类型：
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作者：
Gravina, Giovanni Luca;Mancini, Andrea;Festuccia, Claudio
背景大多数前列腺癌（Pca）患者的发病率可归因于骨转移事件，这构成了重大的临床障碍。因此，更好地了解这一现象是必要的，可能有助于开发新的治疗策略。基质细胞衍生因子1（SDF-1）及其受体CXCR 4已被认为是骨吸收和骨转移发展的调节因子，这表明能够抑制这种信号传导途径的药物可用作药物治疗。在这项研究中，我们研究了两种CXCR 4受体拮抗剂，普乐沙福和CTE 9908，是否可能影响Pca诱导的骨转移性疾病在临床前实验模型方法为了验证CXCR 4抑制影响Pca转移性疾病的假设，选择性CXCR 4化合物，普乐沙福，和CTE 9908，在临床前模型中进行了测试，已知产生骨病变。此外，在许多来源于Pca的原发肿瘤、淋巴结和骨转移的人组织中以及在一组广泛的人Pca细胞系中分析CXCR 4和SDF-1的表达水平，以获得非致瘤性和致瘤性表型。在人类Pca样品中也观察到这种差异表达。体外证据支持骨微环境产生的因子在前列腺微环境方面差异性维持CXCR 4和SDF 1表达的假设，决定了普乐沙福的疗效增加。SDF 1中和抗体的使用大大降低了与骨基质细胞（BMSc）共培养的细胞中CXCR 4表达的增加，并在较小程度上降低了与前列腺基质细胞（HPSc）共培养的细胞中CXCR 4表达的增加，并部分降低了SDF 1-普乐沙福的疗效。SDF-1诱导肿瘤细胞迁移和侵袭，以及MMP-9、MMP-2和uPA表达，Plerixafor可降低这些表达。普乐沙福和CTE 9908给药后，X射线可检测骨病变的发生率显著降低。Kaplan-Meier概率图显示，普乐沙福和CTE 9908给药小鼠的总生存期显著改善。由于Plerixafor和CTE 9908治疗，胫骨内注射后PC 3和PCb 2肿瘤细胞的骨内生长减少，与骨质溶解和mTRAP和I型胶原片段（CTX）的血清水平降低相关，结论我们的报告提供了CXCR 4抑制剂对Pca骨形成和进展的潜在活性的新信息，和软组织转移，并支持这些抑制剂在发生临床明显骨病变的高风险男性中使用的生物学原理。前列腺75：1227-1246，2015年。(c)2015 Wiley Periodicals，Inc.
BACKGROUNDThe majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments. In this study we studied if two CXCR4 receptor antagonists, Plerixafor and CTE9908, may affect bone metastatic disease induced by Pca in preclinical experimental modelsMETHODSTo verify the hypothesis that CXCR4 inhibition affects Pca metastatic disease, selective CXCR4 compounds, Plerixafor, and CTE9908, were tested in preclinical models known to generate bone lesions. Additionally, the expression levels of CXCR4 and SDF-1 were analyzed in a number of human tissues derived from primary tumors, lymph-nodes and osseous metastases of Pca as well as in a wide panel of human Pca cell lines to non-tumorigenic and tumorigenic phenotype.RESULTSBone-derived Pca cells express higher CXCR4 levels than other Pca cell lines. This differential expression was also observed in human Pca samples. In vitro evidence supports the hypothesis that factors produced by bone microenvironment differentially sustain CXCR4 and SDF1- expression with respect to prostate microenvironment determining increased efficacy toward Plerixafor. The use of SDF1- neutralizing antibodies greatly reduced the increase of CXCR4 expression in cells co-cultured with bone stromal cells (BMSc) and to a lesser extent in cells co-cultured with prostate stromal cells (HPSc) and partially reduced SDF1- Plerixafor efficacy. SDF-1 induced tumor cell migration and invasion, as well as MMP-9, MMP-2, and uPA expression, which were reduced by Plerixafor. The incidence of X-ray detectable bone lesions was significantly reduced following Plerixafor and CTE9908 treatment Kaplan-Meier probability plots showed a significant improvement in the overall survival of mice treated with Plerixafor and CTE9908. The reduced intra-osseous growth of PC3 and PCb2 tumor cells after intratibial injection, as a result of Plerixafor and CTE9908 treatment, correlated with decreased osteolysis and serum levels of both mTRAP and type I collagen fragments (CTX), which were significantly lower with respect to controls.CONCLUSIONSOur report provides novel information on the potential activity of CXCR4 inhibitors on the formation and progression of Pca bone and soft tissue metastases and supports a biological rationale for the use of these inhibitors in men at high risk to develop clinically evident bone lesions. Prostate 75:1227-1246, 2015. (c) 2015 Wiley Periodicals, Inc.