Ccl9, also known as chemokine (C-C motif) ligand 9, is a chemokine that plays a significant role in regulating leukocyte chemotaxis and tissue inflammation. It is involved in various biological processes such as the immune response, cancer development, and organ fibrosis. Ccl9 exerts its functions mainly through binding to its receptors CCR1 and CCR3, thus activating related signaling pathways [1,2].

In cancer research, Ccl9 shows diverse roles. In a murine H22 orthotopic hepatoma model, splenic macrophages secrete Ccl9, which recruits myeloid-derived suppressor cells (MDSCs) to the spleen via the CCR1-dependent pathway, facilitating tumor growth [4,6]. In pancreatic ductal adenocarcinoma, oncogenic KrasG12D upregulates Ccl9, promoting pancreatic acinar-to-ductal metaplasia through increasing reactive oxygen species and metalloproteinases levels [2]. However, in a murine model of colon cancer, overexpression of Ccl9 in CT26.CL25 colon cancer cells led to a decline in tumor growth in vivo, possibly by interacting with host immune cells [3]. In chronic kidney disease, Ccl9 is upregulated early, and its blockade during CKD initiation enhances kidney inflammation and fibrosis [5].

In conclusion, Ccl9 has complex functions in different disease conditions. Gene-targeted mouse models, such as those with Ccl9 knockdown or overexpression, have been crucial in revealing its roles in cancer development and progression, as well as in kidney disease. These studies provide valuable insights into potential therapeutic strategies targeting Ccl9 for treating related diseases.

References:

1. Niu, Boning, Tian, Tianyi, Wang, Lu, Zhou, Hu, Zhang, Zhiping. 2024. CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-β. In Acta pharmaceutica Sinica. B, 14, 3711-3729. doi:10.1016/j.apsb.2024.05.009. https://pubmed.ncbi.nlm.nih.gov/39220887/

2. Liou, Geou-Yarh, Byrd, Crystal J, Storz, Peter, Messex, Justin K. 2024. Cytokine CCL9 Mediates Oncogenic KRAS-Induced Pancreatic Acinar-to-Ductal Metaplasia by Promoting Reactive Oxygen Species and Metalloproteinases. In International journal of molecular sciences, 25, . doi:10.3390/ijms25094726. https://pubmed.ncbi.nlm.nih.gov/38731942/

3. Łazarczyk, Marzena, Kurzejamska, Ewa, Mickael, Michel-Edwar, Gaciong, Zbigniew, Religa, Piotr. 2023. Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer. In Current issues in molecular biology, 45, 3446-3461. doi:10.3390/cimb45040226. https://pubmed.ncbi.nlm.nih.gov/37185750/

4. Li, Baohua, Li, Wenjuan, Liang, Yingxue, Kong, Guangyao, Li, Zongfang. 2023. Spleen-Derived CCL9 Recruits MDSC to Facilitate Tumor Growth in Orthotopic Hepatoma Mice. In Global medical genetics, 10, 348-356. doi:10.1055/s-0043-1777327. https://pubmed.ncbi.nlm.nih.gov/38046278/

5. Hemmers, Christian, Schulte, Corinna, Wollenhaupt, Julia, Jankowski, Joachim, Noels, Heidi. 2022. Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis. In Biomedicines, 10, . doi:10.3390/biomedicines10020420. https://pubmed.ncbi.nlm.nih.gov/35203629/

6. Li, Baohua, Zhang, Shu, Huang, Na, Yang, Jun, Li, Zongfang. 2018. CCL9/CCR1 induces myeloid‑derived suppressor cell recruitment to the spleen in a murine H22 orthotopic hepatoma model. In Oncology reports, 41, 608-618. doi:10.3892/or.2018.6809. https://pubmed.ncbi.nlm.nih.gov/30365155/