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Chemokine 25–induced signaling suppresses colon cancer invasion and metastasis
Huanhuan Joyce Chen, … , Xiling Shen, Steven Lipkin
Huanhuan Joyce Chen, … , Xiling Shen, Steven Lipkin
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3184-3196. https://doi.org/10.1172/JCI62110.
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Research Article Oncology Article has an altmetric score of 14

Chemokine 25–induced signaling suppresses colon cancer invasion and metastasis

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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 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.

Authors

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

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Figure 6

NOTCH downregulates CCR9/CCL25 axis signaling in early-stage CCICs and increases extra-GI tumor formation.

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NOTCH downregulates CCR9/CCL25 axis signaling in early-stage CCICs and i...
(A) CCR9 mRNA levels in CCR9+ cells of early-stage CCIC1 and CCIC2 in response to JAG1-induced NOTCH activation using quantitative PCR. HES1 was used as positive control. **P < 0.001. (B) CCR9 protein levels in CCR9+ early-stage CCIC1 and CCIC2 cotreated with or without proteasome inhibitor (100 nM PS341, 4 hours before harvest), in response to JAG1-induced NOTCH activation using Western blot. HES1 was used as positive control. Lanes were run on the same gel but were noncontiguous (white lines). (C) Pretreatment of CCIC with 5 μg/ml JAG1 peptide for 8 hours suppresses CCL25-dependent chemotaxis in Boyden chamber assay. *P < 0.0001, compared with control by 1-way ANOVA; **P < 0.001, compared with CCL25 alone (n = 3). Error bars indicate SEM. (D) Pretreatment of CCR9+ CCICs with 2 μg/ml JAG1 peptide for 8 hours suppresses CCR9 protein, and CCL25 induces phospho-AKT (Ser473) levels, with essentially no change in total AKT levels. Western blot analysis used anti-human CCR9, phospho-AKT, total AKT (AKT1, AKT2, AKT3), NICD, and HES1 antibodies. β-Actin was used as a loading control. (E) CCICs carrying GFP-NOTCH reporter were sorted into NOTCH high and low subpopulations by FACS and injected into tail veins of NOD/SCID mice. NOTCH high CCICs form more extra-GI tumors, while NOTCH low CCICs form more GI tumors. Error bars indicate SEM. **P < 0.01, *P < 0.05, compared with each other. Also see Supplemental Figures 6 and 7.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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