Chemokines help regulate tumor cell invasion and metastasis. Here, we show that the Chemokine 25/Chemokine Receptor 9 (CCL25/CCR9) axis suppresses colon cancer (CRC) invasion and metastasis. CCR9 protein expression levels are highest in colon adenomas, and progressively decrease in invasive and metastatic CRCs. CCR9 is expressed in both primary tumor cell cultures and colon cancer initiating cell lines (CCIC) derived from early stage (I/II) CRCs. CCL25 stimulates cell proliferation through a network of transcription factors downstream of AKT signaling. In vivo, systemically injected CCR9+ early stage CCIC spontaneously form orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling prevents CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extra-intestinal tumor multiplicity. NOTCH signaling, which promotes CRC metastasis, increases extra-intestinal tumor multiplicity by stimulating CCR proteosomal degradation. These data provide insights into the mechanisms that regulate CRC progression, invasion and metastasis and describe a novel in vivo experimental system to study these processes. Our findings also raise a safety concern for ongoing Inflammatory Bowel Disease clinical trials using CCR9 antagonists.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5207. doi:1538-7445.AM2012-5207