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.
View: Text | PDF
Research Article Oncology

Chemokine 25–induced signaling suppresses colon cancer invasion and metastasis

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

×

Figure 2

Early-stage CCICs form orthotopic xenograft tumors in mouse intestine and colon and other sites.

Options: View larger image (or click on image) Download as PowerPoint
Early-stage CCICs form orthotopic xenograft tumors in mouse intestine an...
(A) Postmortem analysis of NOD/SCID mice with tail vein–injected CCICs (original magnification, ×4). Arrows indicate CCIC tumors in lung (white spots; top part of photo) and intestine (bottom part of photo). Small bowel is distended and inflamed. (B) Close-up image of mouse abdomen showing (a) distended small intestine loop proximal to CCIC tumor obstruction with adhesion (indicated by arrows) to adjacent (non-obstructed and grossly normal) small intestine loop and (b) Pneumatosis intestinalis from bacterial stasis in right colon proximal to another CCIC obstruction (original magnification, ×4). (C) High-power light microscopy close-up image of CCIC jejunal adenocarcinoma. Scale bars: 0.5 mm. (D) Multiple CCIC tumors with histopathology in small intestine, (E and F) colon, and (G) lung. Arrow denotes adenocarcinomas in D–G. Scale bars: 100 μm. (H) Xenograft tumor incidence by site of implantation in mice injected with CCICs or CRC cell lines. *P < 0.01, **P < 0.001, compared with non-CCIC. Error bars indicate SEM.