Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis.

Published

Journal Article

Chemotactic cytokines (chemokines) can help regulate tumor cell invasion and metastasis. Here, we show that chemokine 25 (CCL25) and its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal cancer (CRC) invasion and metastasis. We found that CCR9 protein expression levels were highest in colon adenomas and progressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cell cultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastatic CRC. CCL25 stimulated cell proliferation by activating AKT signaling. In vivo, systemically injected CCR9+ early-stage CCICs led to the formation of orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling inhibited CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 and CCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimental system to study CRC progression in the native colon microenvironment.

Full Text

Duke Authors

Cited Authors

  • Chen, HJ; Edwards, R; Tucci, S; Bu, P; Milsom, J; Lee, S; Edelmann, W; Gümüs, ZH; Shen, X; Lipkin, S

Published Date

  • September 2012

Published In

Volume / Issue

  • 122 / 9

Start / End Page

  • 3184 - 3196

PubMed ID

  • 22863617

Pubmed Central ID

  • 22863617

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI62110

Language

  • eng