JAK-STAT Blockade Inhibits Tumor Initiation and Clonogenic Recovery of Prostate Cancer Stem-like Cells

被引：168

作者：

Kroon, Paula ^{[1
]}

Berry, Paul A. ^{[1
]}

Stower, Michael J. ^{[3
]}

Rodrigues, Greta ^{[4
]}

Mann, Vincent M. ^{[5
]}

Simms, Matthew ^{[2
,5
]}

Bhasin, Deepak ^{[6
]}

Chettiar, Somsundaram ^{[6
]}

Li, Chenglong ^{[6
]}

Li, Pui-Kai ^{[6
]}

Maitland, Norman J. ^{[1
]}

Collins, Anne T. ^{[1
]}

机构：

[1] Univ York, Dept Biol, Yorkshire Canc Res Unit, York YO10 5DD, N Yorkshire, England

[2] Univ York, Hull York Med Sch, York YO10 5DD, N Yorkshire, England

[3] York Hosp NHS Trust, Dept Urol, York, N Yorkshire, England

[4] Hull Royal Infirm, Dept Pathol, Kingston Upon Hull, England

[5] Castle Hill Hosp, Hull & East Yorkshire Hosp NHS Trust, Cottingham, England

[6] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA

来源：

CANCER RESEARCH | 2013年 / 73卷 / 16期

关键词：

GROWTH-SUPPRESSIVE ACTIVITY; MULTIPLE-MYELOMA CELLS; PROSPECTIVE IDENTIFICATION; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTORS; KINASE INHIBITOR; ELEVATED LEVELS; SMALL-MOLECULE; IN-VIVO; INTERLEUKIN-6;

D O I：

10.1158/0008-5472.CAN-13-0874

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：5288 / 5298

页数：11

共 49 条

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