PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy.
PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy.
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DOI：
10.18632/oncotarget.6955
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发表时间：
2016-02-16
期刊：
影响因子：
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通讯作者：
Waugh DJ
中科院分区：
文献类型：
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作者：
Armstrong CW;Maxwell PJ;Ong CW;Redmond KM;McCann C;Neisen J;Ward GA;Chessari G;Johnson C;Crawford NT;LaBonte MJ;Prise KM;Robson T;Salto-Tellez M;Longley DB;Waugh DJ
PTEN缺失是前列腺癌(CAP)放疗后复发的预后指标。肿瘤相关巨噬细胞(TAMs)的浸润与前列腺癌根治术后无病生存率降低有关。然而，PTEN缺失、浸润与CAP细胞放射疗效之间的关系仍有待研究。手术切除的Gleason 7肿瘤的免疫组织化学和分子分析证实，PTEN缺失与CXCL8表达增加和巨噬细胞浸润有关。然而，PTEN状态与CAP细胞表达其他炎症标志物，包括肿瘤坏死因子-α的相关性不明显。在体外，暴露于从照射的PTEN空帽细胞获得的条件培养液可以诱导巨噬细胞样THP-1细胞的趋化，这种反应部分地被CXCL8抑制而减弱。与THP-1细胞共培养后，DU145细胞的放射敏感性略有降低。细胞因子谱显示，无论PTEN状态如何，CAP细胞都能结构性分泌肿瘤坏死因子-α，IR诱导的肿瘤坏死因子-α也能从THP-1细胞分泌。THP-1衍生的肿瘤坏死因子-α可增加CAP细胞中包括细胞凋亡抑制蛋白-1(CIMP-1)在内的抗凋亡蛋白κ-1的表达，并增加NF-α的促存活活性，这种作用可被肿瘤坏死因子-DNA中和抗体减弱。新的IAP拮抗剂AT-IAP可降低CAP细胞基础表达和肿瘤坏死因子-α诱导的CIAP-1的表达，将肿瘤坏死因子-α信号从支持生存信号转换为支持凋亡信号，并增加CAP细胞与THP-1细胞的辐射敏感性。我们的结论是，靶向CIAP-1可以克服CAP细胞对凋亡的抵抗，是利用α缺失的CAP细胞富含的微环境中的高肿瘤坏死因子-PTEN信号来增强放射治疗反应的理想途径。
PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.