JAK-STAT Blockade Inhibits Tumor Initiation and Clonogenic Recovery of Prostate Cancer Stem-like Cells
JAK-STAT Blockade Inhibits Tumor Initiation and Clonogenic Recovery of Prostate Cancer Stem-like Cells
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DOI：
10.1158/0008-5472.can-13-0874
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发表时间：
2013-08-15
期刊：
影响因子：
11.2
通讯作者：
Collins, Anne T.
中科院分区：
文献类型：
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作者：
Kroon, Paula;Berry, Paul A.;Collins, Anne T.
白细胞介素（IL）-6过表达和组成性STAT 3激活发生在许多癌症中，包括前列腺癌。然而，它们对前列腺干细胞和祖细胞的贡献尚未被探索。在这项研究中，我们发现前列腺癌患者的干细胞样细胞分泌的IL-6水平高于非肿瘤性前列腺。肿瘤分级不影响表达或分泌水平。干细胞和祖细胞表达IL-6受体gp 80，同时表达pSTAT 3。通过抗IL-6抗体siltuximab（CNTO 328）或LLL 12（一种特异性pSTAT 3抑制剂）阻断活化的STAT 3，可抑制高级别疾病患者干细胞样细胞的集落形成。在用于确定pSTAT 3抑制的体内作用的鼠异种移植物模型中，LLL 12处理有效地消除了患者来源的去势抵抗性肿瘤的生长。我们的研究结果表明，前列腺癌中最原始的细胞需要pSTAT 3才能生存，从而使STAT 3作为治疗晚期前列腺癌的治疗靶点合理化。Cancer Res; 73（16）; 5288-98. (C)2013年AACR。
Interleukin (IL)-6 overexpression and constitutive STAT3 activation occur in many cancers, including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from patients with prostate cancer secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high-grade disease. In a murine xenograft model used to determine the in vivo effects of pSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require pSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer. Cancer Res; 73(16); 5288-98. (C) 2013 AACR.