CCR9 in cancer: oncogenic role and therapeutic targeting

Abstract

Cancer is currently one of the leading causes of death worldwide and is one of the most challenging major public health problems. The main challenges faced by clinicians in the management and treatment of cancer mainly arise from difficulties in early diagnosis and the emergence of tumor chemoresistance and metastasis. The structures of chemokine receptor 9 (CCR9) and its specific ligand chemokine ligand 25 (CCL25) have been elucidated, and, interestingly, a number of studies have demonstrated that CCR9 is a potential tumor biomarker in diagnosis and therapy, as it has been found to be highly expressed in a wide range of cancers. This expression pattern suggests that CCR9 may participate in many important biological activities involved in cancer progression. Researchers have shown that CCR9 that has been activated by its specific ligand CCL25 can interact with many signaling pathways, especially those involved in tumor chemoresistance and metastasis. This review, therefore, focuses on CCR9 induction activity and summarizes what is currently known regarding its role in cancers and its potential application in tumor-targeted therapy.

Fig. 1

The structures of CCR9 and CCL25. The molecular structures of CCR9 (a) and CCL25 (b) from the UniProt web site (http://www.proteinmodelportal.org/query/uniprot). The simulated interaction of CCL25 and CCR9 was performed by MGLTools 1.5.6 software based on the structures of CCR9 and CCL25 (c)

Fig. 2

Diagram summarizing the reviewed mechanisms by which CCR9 induces different aspects of tumor chemoresistance. The interaction of CCL25/CCR9 can induce tumor chemoresistance via the PI3K-AKT-(GSK-3β/mTOR/NF-κB/β-catenin) and JAK-STAT pathways. The interactions between P-gp, ERM, and F-actin can induce tumor chemoresistance via the CCL25/CCR9 pathway

Fig. 3

Diagram summarizing the reviewed mechanisms by which CCR9 induces different aspects of tumor metastasis. a The interaction of CCL25 and CCR9 can induce tumor metastasis via the RAS-MAPK-MMP pathway, the RhoA-Rock-MLC pathway, and ezrin signaling. b CCR9-high-expressing tumor cells are targeted to the small intestine and gastrointestinal tract by CCL25/CCR9 signaling. The solid arrows indicate that these signaling pathways have confirmed; the dashed arrows show that these signaling pathways need to be further validation

Fig. 4

Diagram summarizing the reviewed mechanisms by which CCR9 induces different aspects of tumor chemoresistance and metastasis. The solid arrows indicate that these signaling pathways have confirmed; the dashed arrows show that these signaling pathways need to be further validation

Fig. 5

The mechanism of PE38-induced cell death. The immunotoxin is internalized when it binds with its specific receptor via the endolysosomal system to the Golgi, and it is further transported to the endoplasmic reticulum. Then, it can cause ADP ribosylation and elongation factor 2 inactivation to halt protein synthesis and eventually lead to cell death