Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic-and Colitis-Colon Cancer Stem Cells

被引:45
作者
Fisher, Robert C. [1 ]
Bellamkonda, Kishan [1 ]
Molina, L. Alex [1 ]
Xiang, Shao [1 ]
Liska, David [1 ,2 ]
Sarvestani, Samaneh K. [1 ]
Chakrabarti, Susmita [3 ]
Berg, Annamarie [1 ]
Jorgensen, Marda L. [4 ]
Hatala, Denise [5 ]
Chen, Sugong [6 ]
Aiello, Alexandra [7 ]
Appelman, Henry D. [8 ]
Scott, Edward W. [9 ]
Huang, Emina H. [1 ,2 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, 9500 Euclid Ave, Cleveland, OH 44195 USA
[2] Cleveland Clin, Dept Colorectal Surg, Cleveland, OH 44106 USA
[3] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA
[4] Univ Florida, Dept Pediat, Gainesville, FL USA
[5] Cleveland Clin, Lerner Res Inst, Immunochem Core, Cleveland, OH 44106 USA
[6] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
[7] Cleveland Clin, Quantitat Hlth Sci, Cleveland, OH 44106 USA
[8] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[9] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA
来源
NEOPLASIA | 2019年 / 21卷 / 03期
基金
美国国家卫生研究院;
关键词
COLORECTAL-CANCER; IN-VITRO; INTERLEUKIN-8; CXCR1; PROLIFERATION; PROGRESSION; EXPRESSION; MIGRATION; SURVIVAL; TUMORS;
D O I
10.1016/j.neo.2018.12.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC-and pCCSC-induced proliferation and angiogenesis.
引用
收藏
页码:269 / 281
页数:13
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