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

Published

Journal Article

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.

Full Text

Cited Authors

  • Fisher, RC; Bellamkonda, K; Alex Molina, L; Xiang, S; Liska, D; Sarvestani, SK; Chakrabarti, S; Berg, A; Jorgensen, ML; Hatala, D; Chen, S; Aiello, A; Appelman, HD; Scott, EW; Huang, EH

Published Date

  • March 2019

Published In

Volume / Issue

  • 21 / 3

Start / End Page

  • 269 - 281

PubMed ID

  • 30738331

Pubmed Central ID

  • 30738331

Electronic International Standard Serial Number (EISSN)

  • 1476-5586

International Standard Serial Number (ISSN)

  • 1522-8002

Digital Object Identifier (DOI)

  • 10.1016/j.neo.2018.12.007

Language

  • eng