Chemokine 25 - Induced signaling suppresses colon cancer invasion and metastasis

Huanhuan Joyce Chen, Robert Edwards, Serena Tucci, Pengcheng Bu, Jeff Milsom, Sang Lee, Winfried Edelmann, Zeynep H. Güm̈us, Xiling Shen, Steven Lipkin

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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 andprogressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cellcultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastaticCRC. 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 increasingextraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 andCCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimentalsystem to study CRC progression in the native colon microenvironment.

Original languageEnglish (US)
Pages (from-to)3184-3196
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number9
DOIs
StatePublished - Sep 4 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Chen, H. J., Edwards, R., Tucci, S., Bu, P., Milsom, J., Lee, S., Edelmann, W., Güm̈us, Z. H., Shen, X., & Lipkin, S. (2012). Chemokine 25 - Induced signaling suppresses colon cancer invasion and metastasis. Journal of Clinical Investigation, 122(9), 3184-3196. https://doi.org/10.1172/JCI62110