CXCR4 in human osteosarcoma malignant progression. The response of osteosarcoma cell lines to the fully human CXCR4 antibody MDX1338
CXCR4 in human osteosarcoma malignant progression. The response of osteosarcoma cell lines to the fully human CXCR4 antibody MDX1338
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DOI：
10.1016/j.jbo.2019.100239
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Pazzaglia, Laura
中科院分区：
文献类型：
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作者：
Pollino, Serena;Palmerini, Emanuela;Pazzaglia, Laura
骨肉瘤(OS)是最常见的原发性骨恶性肿瘤，30%的病例发生转移，5年生存率为25-30%。尽管术前和术后化疗可改善骨肉瘤(OS)的预后，但高毒性和天然和获得性耐药是治疗失败的首要原因。新的预测和治疗生物标志物的鉴定可能会提高药物敏感性并更好地控制局部和转移性疾病。有证据表明 CXCR4 受体通过结合其配体 CXCL12 激活肿瘤恶性肿瘤的下游关键终点，我们首先研究了 OS 活检中 CXCR4 表达与患者临床数据相关的人类 OS 进展。通过实时PCR和免疫组织化学，我们发现CXCR4基因和蛋白的高水平表达与OS进展显着相关，强调了CXCR4/CXCL12轴在肿瘤预后中的作用。单变量分析支持了这一点，单变量分析显示，CXCR4 基因高表达的 OS 患者局部和/或全身复发的可能性较高，并且与 CXCR4 蛋白染色强度评分增加相关的转移风险显着增加。其次，为了研究 CXCR4 作为新治疗策略靶点的作用，我们评估了 OS 细胞对全人 CXCR4 抗体 MDX1338 的反应。在该研究中，我们还纳入了研究最多的 CXCR4 拮抗剂 AMD3100。 在富含 CXCL12 的 BM-MCS-CM（骨髓源性间充质干条件培养基）中培养的 CXCR4 阳性 OS 细胞中，药物暴露后细胞增殖减少达对照的 30%-40%。然而，CXCR4 抑制剂孵育后，p53 阳性 U2OS 和 143B 细胞凋亡增加，而经处理的 SAOS-2 细胞未见变化，其也呈现不同的标记谱。 p53 在 CXCR4 抑制剂的细胞凋亡反应中的作用通过 U2OS 细胞系中的 p53 沉默得到证实。我们的数据表明，对抗 CXCR4 药物的反应可能受到遗传背景和标记谱的影响，从而诱导肿瘤细胞和环境之间的不同串扰。与细胞凋亡增加相关的细胞周期进展延迟可能会使 p53 阳性细胞对常规疗法敏感，体内临床前实验正在进行中，旨在为人类 OS 提出新的联合靶向疗法。
Osteosarcoma (OS) is the most frequent primary malignant tumour of bone and metastases occur in 30% of cases, the 5-year survival rate is 25-30%.Although pre- and post-operative chemotherapy has improved prognosis in osteosarcoma (OS), high toxicity and natural and acquired drug-resistance are the first cause of treatment failure. The identification of new predictive and therapeutic biomarkers may increase drug sensitivity and better control localized and metastatic disease. By the evidence that CXCR4 receptor by binding its ligand CXCL12 activates downstream critical endpoints for tumour malignancy, we first studied human OS progression correlating CXCR4 expression in OS biopsy with patient clinical data. By Real-time PCR and immunoistochemistry we found that high levels of CXCR4 gene and protein expression significantly correlated with OS progression, emphasizing the role of CXCR4/CXCL12 axis in tumour prognosis. This was supported by univariate analyses that showed a higher probability of local and/or systemic relapse in OS patients with a high CXCR4 gene expression and a significant increase of metastasis risk associated with an increasing score of CXCR4 protein staining intensity. Secondarily, to study the role of CXCR4 as a target for new therapeutic strategies, we evaluated the response of OS cells to the fully human CXCR4 antibody, MDX1338. In the study we also included AMD3100, the most studied CXCR4 antagonist.In CXCR4-positive OS cells cultured in CXCL12-rich BM-MCS-CM (bone marrow-derived mesenchymal stem conditioned medium), a decrease of cell proliferation up to 30%-40% of control was seen after drug exposure. However, an increase of apoptosis was seen in p53-positive U2OS and 143B after CXCR4 inhibitor incubation, while no changes were seen in treated SAOS-2 cells which also present a different labeling profile. The role of p53 in apoptotic response to CXCR4 inhibitors was confirmed by p53 silencing in U2OS cell line. Our data suggest that the response to anti-CXCR4 agents could be influenced by the genetic background and labeling profile which induces a different cross-talk between tumour cells and environment. The delay in cell cycle progression associated with increased apoptosis could sensitize p53-positive cells to conventional therapy and in vivo preclinical experiments are on going with the aim to suggest new combined target therapies in human OS.