Open Access

The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review)

  • Authors:
    • Cong Wang
    • Zhenghuan Liu
    • Zhihui Xu
    • Xian Wu
    • Dongyang Zhang
    • Ziqi Zhang
    • Jianqin Wei
  • View Affiliations

  • Published online on: June 4, 2018     https://doi.org/10.3892/ol.2018.8896
  • Pages: 2071-2077
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Chemokine ligand 25 (CCL25) and chemokine receptor 9 (CCR9) are important regulators of migration, proliferation and apoptosis in leukocytes and cancer cells. Blocking of the CCR9/CCL25 signal has been demonstrated to be a potential novel cancer therapy. Research into CCR9 and CCL25 has revealed their associated upstream and downstream signaling pathways; CCR9 is regulated by several immunological factors, including NOTCH, interleukin 2, interleukin 4 and retinoic acid. NOTCH in particular, has been revealed to be a crucial upstream regulator of CCR9. Furthermore, proteins including matrix metalloproteinases, P‑glycoprotein, Ezrin/Radixin/Moesin and Livin are regulated via phosphatidylinositol‑3 kinase/ protein kinase B, which are in turn stimulated by CCR9/CCL25. This is a review of the current literature on the functions and signaling pathways of CCR9/CCL25.

Introduction

The cDNA of CCR9 was submitted to Genbank (Genbank no. HSU45982) by Lautens in 1996 as G-protein-coupled-receptor-9-6 (GPR-9-6). The expression and function of GPR-9-6 was investigated by Zaballos et al (1) in 1999. GPR-9-6 was renamed as CCR9, due to its similarity in structure and sequence to chemokine receptor 6 (CCR6), chemokine receptor 7 (CCR7) and STRL33/Bonzo (1). Furthermore, in vitro stimulation of CCR9 with thymus-expressing chemokine (TECK) induced intra-cytoplasmic calcium mobilization and migration of 293 cells (1). TECK, also known as CCL25, was discovered in thymic dendritic cells in 1997 (2), and was subsequently confirmed to be the sole ligand of CCR9 (3). CCR9 expression was revealed to be low in human and murine spleen and lymph nodes but high in thymic tissues (1).

Further studies demonstrated that CCR9 is highly expressed in the colon, small intestine and several other tissues involved in the development and maturation of T cells, macrophages and dendritic cells (DCs) (49). CCR9 signaling may therefore have an influence on processes, including inflammatory responses and transplantation rejection (1012). Furthermore, CCR9 has been demonstrated to influence cancer cell migration, proliferation and drug resistance (1315). This is a review of the current literature on the function of CCR9 in leukocytes and cancer cells.

Chemokine receptor 9 in leukocytes

The function of CCR9 in different leukocyte subtypes is relatively comparable (Fig. 1).

CCR9+ DCs migrate to the small intestine and colon to interact with other leukocytes, particularly T cells, to induce local inflammation (46). Thymic epithelial cells are the principle source of CCL25 (7); however, thymic DCs also secrete CCL25, which may contribute toward DC-T cell interactions (2).

CCR9 serves an important role in the regulation of T cells. CCR9 (16) and CCR7 (17,18) have been demonstrated to contribute toward the recruitment of T cells to the thymus. T cell development is also regulated by CCR9 (19). CCR9-knockdown skewed T cell subgroup ratios; thymic αβ-T cell development was not affected in CCR9−/− mice, whereas the number of γδ-T cells located in the intestine was increased (19). In addition, CCR9 suppressed differentiation of forkhead box protein 3+ regulatory T cells (20). Several T cell functions were revealed to be CCR9-dependent; CD4+ CCR9+ T helper cells expressed interleukin 21 (IL-21), inducible T cell co-stimulator, transcription factor B-cell CLL/lymphoma 6 and muscular aponeurotic fibrosarcoma (Maf), and supported B cell antibody production (21). In splenic T cells, blocking CCR9/CCL25 signaling reduced secretion of interferon-γ (IFN-γ) (12). This may serve a role in certain immunological processes, including transplant rejection and the inflammatory response. Anti-CCL25 antibodies decreased the infiltration of cells around skin allografts, which prolonged the survival of the graft (12). Recruitment of T cells to the intestine and colon was demonstrated to be CCR9-dependent (22,23). CCR9+ T cells were recruited to inflammatory bowel disease lesions, and were revealed to be associated with disease activity (10). Similarly, during Aggregatibacter actinomycetemcomitans serotype b infection, CCR9 expression was increased in T cells (11).

Retinoic acid (RA) has been demonstrated to serve a role in DC-T cell interactions. Several studies revealed that CCR9 expression fluctuated at different stages of DC development (9,24). Furthermore, several other studies demonstrated that DCs produced RA, which mediated CCR9 expression in T cells (25) and induced interleukin 10 (IL-10) expression in α4β7+ CCR9+ T cells (26). T cells were also mediated by RA directly via the RA receptor, which upregulated CCR9 expression (27,28). Therefore, decreased expression of the RA receptor was associated with a reduction in CCR9 expression and an attenuation of graft-versus-host disease (29).

Naïve B cell migration has been demonstrated to be regulated by CCR9 (30). A high CCR9 expression has also been revealed in memory B cells (31). Epstein-Barr virus-infected B cells demonstrated increased CCR9 expression (32). However, CCR9/CCL25 signaling does not appear to be vital for B development, as maturation of B cells was not impaired in CCR9−/− mice (19).

Macrophages migrate to infected peritoneal (33) and acute colitis lesions (6). Macrophages recruited by CCR9, which produced tumor necrosis factor-α (TNF-α), were crucial for liver fibrosis (34). CCR9 expression in these recruited macrophages was regulated by their interaction with hepatic stellate cells (35).

In summary, CCR9 serves a role in the migration, maturation and function of leukocytes.

Chemokine receptor 9 in cancer cells

Following the discovery of CCR9/CCL25 signaling pathways in leukocytes, oncology researchers revealed that CCR9 promotes invasion, migration, anti-apoptosis and drug-resistance in several types of tumors (Fig. 1).

CCR9/CCL25 signaling has been rigorously studied in hematological malignancies. In T cell lineage acute lymphocytic leukemia (T-ALL) CD4+ cells, CCR9 was highly expressed, while T cell chronic lymphocytic leukemia (T-CLL) CD4+ cells moderately expressed CCR9, and a low CCR9 expression was demonstrated in normal CD4+ T cells (36). The CCR9+ T-ALL Jurkat, MOLT-4, CEM, SupT1, TALL-1 and DND41 cell lines were revealed to be chemotactic to CCL25 (37). CCL25 stimulation resulted in pseudopodium formation (38), invasion and migration (39). It has been observed that T cells from adult patients with leukemia, that had infiltrated the gastrointestinal tract, were frequently positive for CCR9 (40), which was in line with conclusions from a study that reported that CCR9 expression was associated with gut relapse in pediatric T-ALL (41). Furthermore, CCR9/CCL25 signaling induced P-gp co-localization within the actin cytoskeleton (15). This mechanism led to drug resistance to doxorubicin in the MOLT-4 cell line (15). TNF-α mediated apoptosis was inhibited in CD4+ T-ALL, T-CLL and MOLT-4 cells by CCR9/CCL25 signaling (42). Transformation of gastric mucosa-associated lymphoid tissue to gastric extra-nodal diffuse large B-cell lymphoma was mediated by several chemokines, including CCR9 (43). However, CCR9+ multiple myeloma cells only migrated toward CXC chemokine ligand 12 (CXCL12), indicating a limited function of CCR9 in multiple myeloma (44).

The regulation of melanoma cell metastasis by CCR9/CCL25 signaling remains controversial. Certain studies have demonstrated that CCR9 expression is associated with organ-specific metastasis of melanoma cells (45,46). Melanoma cells that had metastasized to the intestine expressed CCR9, whereas cells that had metastasized to other organs did not (47). Besides the intestine, lymph nodes and skin were the sites where melanoma metastasis often occurred; however, CCR9+ melanoma cells were not observed in these locations (4749). CCR9+ T cells in the melanoma microenvironment have been demonstrated to inhibit metastasis (50). However, certain studies have demonstrated that the function of CCR9 in melanoma was only moderate; the proportion of patients with intestine metastases was low (51), indicating limited organ-specific metastasis (49), which corresponds with the low proportion of CCR9+ cells reported in circulating tumor cells (52). Clinical studies demonstrated that CCR7 and chemokine receptor 10 (CCR10), but not CCR9, were associated with a poorer prognosis (53).

Several types of ovarian carcinoma, including serous adenocarcinoma, serous papillary cystadenoma and endometrioid adenocarcinoma, revealed an increased CCR9 expression compared with normal ovarian tissues (54), and demonstrated migration and invasion potential toward chemotactic gradients of CCL25 (55). Intestinal cells, a source of CCL25, were also a frequent metastatic site for ovarian carcinoma (55).

CCR9 expression of two breast cancer cell lines, MDA-MB-231 and MCF7, and benign tissue, were high, medium and low, respectively, which corresponded with their respective aggressiveness (56). Lymph nodes, bone marrow, lung, liver and brain were frequent sites of breast cancer metastasis, and this process might be regulated by CCR9/CCL25 (5658). CCR9/CCL25 signaling was also revealed to provide a survival advantage to breast cancer cells and inhibited cisplatin-induced apoptosis (59).

In prostate cancer, CCR9 was highly, moderately and lowly expressed in highly invasive LNCaP, moderately invasive PC3 and non-invasive prostatic epithelial cells, respectively (60). CCR9/CCL25 also regulated metastasis (60) and drug-resistance against etoposide (61) in prostate cancer.

In pancreatic cancer, pancreatic intraepithelial neoplasia and pancreatic cancer cells were demonstrated to be CCR9+ (62). The pancreatic cancer PANC-1 cell line was CCR9+, and enhanced invasion was observed following CCL25 treatment (63). Drug-resistance of gemcitabine was stimulated by CCL25 signaling in pancreatic cancer PANC-1, MIAPaCa-2 and AsPC-1 cell lines (14).

In colon cancer, injection of CCR9+ cancer-initiating cells led to formation of gastrointestinal xenograft tumors in mice, whereas blocking CCR9 signaling increased extra-intestinal tumors (13,64).

In the hepatocellular carcinoma cell lines HepG2 and HUH7, CCR9 promoted invasion and migration (65), and might be a marker to predict the prognosis of patients (66).

Similarly, CCR9 could be beneficial in predicting lymph node metastasis and prognosis in lung adenocarcinoma (67). Adenocarcinoma cells revealed a higher migratory and invasive potential in response to CCL25, compared with squamous cell carcinoma cells, which had lower expression of CCR9 and CCL25 (68). Esophageal cancer cells also highly expressed CCR9 and potentially achieved metastasis via CCR9 signaling (69).

Based on these findings, researchers attempted to design CCR9-specific therapies, including CCR9 antagonists, monoclonal antibodies against CCR9, and RNAi of CCR9. Computational modeling of CCR9 antagonists revealed several compounds, one of which inhibited proliferation and invasion of pancreatic cancer cell lines and interacted synergistically with gemcitabine (14). In vivo models revealed that a CCR9 monoclonal antibody increased apoptosis, necrosis of tumor tissue, complement-dependent cytotoxicity and antibody-dependent cytotoxicity by natural killer cells. The antibody was also demonstrated to decrease proliferation and tumor vascularization in MOLT-4 cell lines (70). CCR9 inhibition by RNAi facilitated T cell-associated immunotherapy of breast and pancreatic cancer cell lines (71). Another trial used CCL25 fused with Pseudomonas exotoxin 38 (PE38) toxin, a truncated derivative of Pseudomonas exotoxin A, which induced apoptosis in MOLT-4 cell lines (72).

In summary, CCR9/CCL25 signaling is an important mediator of malignant behaviors in a number of cancer cells. Blocking of CCR9/CCL25 signaling appears to be a potential novel strategy for cancer therapy.

Regulation of chemokine receptor 9

Several immunological factors have been demonstrated to upregulate CCR9, including human T-lymphotropic virus type 1 (HTLV-1)-encoded transcriptional activator Tax (40), RA (25) and Epstein-Barr virus (32). Others, including DAPT (37) and co-stimulation of IL-2 with IL-4 (36), have been revealed to downregulate CCR9. The NOTCH pathway has been revealed to mediate CCR9 expression; however, its function differs in T-ALL and colon cancer (Fig. 2).

NOTCH1 mutations were frequently identified in T-ALL; certain mutations resulted in δ1 ligand-independent NOTCH signaling or lengthened the half-life period of NOTCH1 signaling. Suppression of NOTCH1 by DAPT or RNAi, downregulated CCR9 in the T-ALL cell lines Jurkat, MOLT-4, CEM, SupT1, TALL-1 and DND41 (37).

However, in CCR9+ colon cancer cells, NOTCH signaling was revealed to be reduced compared with that in CCR9 colon cancer cells. Since no significant difference in CCR9 mRNA levels was revealed between CCR9+ and CCR9 cells, it was confirmed that NOTCH lowered CCR9 expression levels by increasing proteasomal degradation (13).

Downstream signaling of chemokine receptor 9/chemokine ligand 25

CCL25 binding led to interactions between CCR9 Gβγ and PI3K, which resulted in activation of Akt (73). In this study, glycogen synthase kinase 3 β (GSK-3β) and forkhead in human rhabdomyosarcoma (FKHR) were demonstrated to be downstream targets of Akt (73), which further influenced the migration, invasion and drug resistance of cancer cells. An alternative stimulation of PI3/Akt by wingless-type protein 5a (Wnt5a) following CCR9/CCL25 interaction was revealed in another study (74), indicating a complex cross-talk between these signaling pathways (Fig. 2).

Mediation of cell invasion and migration by CCR9/CCL25 signaling may involve matrix metalloproteinases (MMPs) (55,56,60), Ras homologue (RhoA)Rho kinase (ROCK)-myosin light chain (MLC) signal (39), Wnt5a (74) and ERM protein family (38). In the ovarian cancer OVCAR-3 and CAOV-3 cell lines, CCR9/CCL25 selectively regulated certain MMPs, which degraded the cell matrix to promote invasion (55). Different patterns of MMP regulation were observed in each cell line; for example, in the OVCAR-3 cell line, expression of MMP-2, 3, 8, 9, 10, 11 and 13 was increased, while MMP-1, 2, 3, 8 and 10 expression levels were elevated in the CAOV-3 cell line (55). A similar mechanism was observed in prostate cancer cell lines (60). CCL25 treatment increased MMP-1 and 2 expression in LNCaP, and MMP-2, 11 and 13 in PC3 cells (60). RhoA-ROCK-MLC signaling, which is associated with cell motility and morphology was stimulated by CCL25 in the MOLT-4 cell line (39). Another pathway has been demonstrated to promote the invasion and migration of MOLT-4 cells; CCL25 induced Wnt5a activation by promoting protein kinase C expression and activation in MOLT-4 cells (74). Activated Wnt5a further induced PI3K/Akt signaling and enhanced cell migration and invasion (74). Invasion-related ERM protein was revealed to be translocated from the cytoplasm to the cell membrane following CCL25 treatment, which contributed to metastasis (38).

Stimulation of drug-resistance by CCL25 might be achieved via P-gp (15), inhibition of GSK-3β and FKHR (59), Livin protein (42), anti-apoptosis protein (PI3K, AKT, extracellular-regulated kinase 1/2 (ERK1/2) and GSK-3β) and caspase-3 (61). P-gp was revealed to promote the extrusion of the antitumor agent, doxorubicin, from the cytoplasm to the extracellular space, resulting in multidrug resistance. This resistance was dependent on interactions between ERM and the actin cytoskeleton following CCL25 stimulation (15). In breast cancer, inhibition of CCR9/CCL25 downstream signaling via GSK-3β or FKHR, significantly improved the chemotherapeutic efficacy of cisplatin (59). Alongside upregulation of anti-apoptosis proteins, including PI3K, Akt, ERK1/2 and GSK-3β, CCL25 also induced drug resistance via downregulation of caspase-3 activity (61). CCL25 suppressed TNF-α-mediated apoptosis by increasing expression of Livin, a member of the inhibitor of apoptosis protein family, via c-jun-NH2-kinase 1 kinase activity (42).

Hypothesis and conclusion

NOTCH and several other signaling proteins regulate CCR9, and CCR9/CCL25 signaling mediates certain downstream proteins to promote metastasis and drug-resistance in cancer cells. Based on the findings that healthy intestine and colon cells physiologically produce CCL25 (2,6,7,75), we hypothesized that CCL25 induces chemotaxis and cell survival signaling in leukocytes and cancer cells. For extra-intestinal cancer, the CCL25 concentration in healthy intestinal micro-environment is higher than that in the primary tumor micro-environment; thus, CCR9+ cancer cells tend to metastasize to the intestine. However, the micro-environment of colon cancer is rich in CCL25 and therefore, CCR9 may be downregulated by NOTCH to reduce chemotaxis and promote metastasis. Investigation of CCL25 levels in the micro-environment of primary and metastatic lesions would further test this hypothesis. Another possible mechanism is based on the seed-earth hypothesis, which states that CCL25 promotes the survival of circulating tumor cells that have metastasized to the intestine.

NOTCH signaling has an opposite function in T-ALL and colon cancer. This contradiction might be explained by the diversity in ligands and downstream signaling. In T-ALL, δ1 is a ligand of NOTCH1 (37), while delta-like 4 (DLL4), Jagged 1 (JAG1) and delta-like proteins 1 (DLK1) are the most probable ligands of NOTCH in colon cancer (13).

In summary, CCR9/CCL25 signaling mediated the migration, invasion and drug resistance of cancer cells. Further studies should focus on elucidating the mechanisms of associated upstream and downstream signaling of CCR9.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

CW and ZL were major contributors in writing the manuscript. ZX, XW, and DZ retrieved, selected the articles, and collected useful information from these articles. ZZ and JW proposed writing this review, made the outline, submitted and revised this manuscript. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

CCR

chemokine receptor

CCL25

chemokine ligand 25

IL

interleukin

RA

retinoic acid

P-gp

P-glycoprotein

ERM

Ezrin/Radixin/Moesin

GPR-9–6

G-protein-coupled-receptor-9-6

TECK

thymus-expressed chemokine

Maf

muscular aponeurotic fibrosarcoma

T-ALL

T cell lineage acute lymphocytic leukemia

T-CLL

T cell chronic lymphocytic leukemia

CXCL12

CXC chemokine ligand 12

PE38

Pseudomonas exotoxin 38

HTLV-1

human T lymphotropic virus type 1

GSK-3β

glycogen synthase kinase 3β

FKHR

forkhead in human rhabdomyosarcoma

Wnt5a

wingless-type protein 5a

RhoA

Ras homologue

ROCK

Rho kinase

DLL4

delta-like 4

JAG1

Jagged 1

DLK1

delta-like proteins 1

References

1 

Zaballos A, Gutiérrez J, Varona R, Ardavín C and Márquez G: Cutting edge: Identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK. J Immunol. 162:5671–5675. 1999.PubMed/NCBI

2 

Vicari AP, Figueroa DJ, Hedrick JA, Foster JS, Singh KP, Menon S, Copeland NG, Gilbert DJ, Jenkins NA, Bacon KB and Zlotnik A: TECK: A novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development. Immunity. 7:291–301. 1997. View Article : Google Scholar : PubMed/NCBI

3 

Yu CR, Peden KW, Zaitseva MB, Golding H and Farber JM: CCR9A and CCR9B: Two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand. J Immunol. 164:1293–1305. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, Pabst O and Förster R: CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci USA. 104:6347–6352. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Mizuno S, Kanai T, Mikami Y, Sujino T, Ono Y, Hayashi A, Handa T, Matsumoto A, Nakamoto N, Matsuoka K, et al: CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice. Immunol Lett. 146:64–69. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Wurbel MA, McIntire MG, Dwyer P and Fiebiger E: CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis. PLoS One. 6:e164422011. View Article : Google Scholar : PubMed/NCBI

7 

Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR, et al: The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur J Immunol. 30:262–271. 2000. View Article : Google Scholar : PubMed/NCBI

8 

Schmutz C, Cartwright A, Williams H, Haworth O, Williams JH, Filer A, Salmon M, Buckley CD and Middleton J: Monocytes/macrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation. Arthritis Res Ther. 12:R1612010. View Article : Google Scholar : PubMed/NCBI

9 

Dursun E, Endele M, Musumeci A, Failmezger H, Wang SH, Tresch A, Schroeder T and Krug AB: Continuous single cell imaging reveals sequential steps of plasmacytoid dendritic cell development from common dendritic cell progenitors. Sci Rep. 6:374622016. View Article : Google Scholar : PubMed/NCBI

10 

Eberhardson M, Marits P, Jones M, Jones P, Karlen P, Karlsson M, Cotton G, Woznica K, Maltman B, Glise H and Winqvist O: Treatment of inflammatory bowel disease by chemokine receptor-targeted leukapheresis. Clin Immunol. 149:73–82. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Alvarez C, Benítez A, Rojas L, Pujol M, Carvajal P, Díaz-Zúñiga J and Vernal R: Differential expression of CC chemokines (CCLs) and receptors (CCRs) by human T lymphocytes in response to different Aggregatibacter actinomycetemcomitans serotypes. J Appl Oral Sci. 23:536–546. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Li J, Xiong T, Xiao R, Xiong A, Chen J, Altaf E, Zheng Y, Zhu G, He Y and Tan J: Anti-CCL25 antibody prolongs skin allograft survival by blocking CCR9 expression and impairing splenic T-cell function. Arch Immunol Ther Exp (Warsz). 61:237–244. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Chen HJ, Edwards R, Tucci S, Bu P, Milsom J, Lee S, Edelmann W, Gümüs ZH, Shen X and Lipkin S: Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis. J Clin Invest. 122:3184–3196. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Lee S, Heinrich EL, Li L, Lu J, Choi AH, Levy RA, Wagner JE, Yip ML, Vaidehi N and Kim J: CCR9-mediated signaling through β-catenin and identification of a novel CCR9 antagonist. Mol Oncol. 9:1599–1611. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Zhang L, Xiao R, Xiong J, Leng J, Ehtisham A, Hu Y, Ding Q, Xu H, Liu S, Wang J, et al: Activated ERM protein plays a critical role in drug resistance of MOLT4 cells induced by CCL25. PLoS One. 8:e523842013. View Article : Google Scholar : PubMed/NCBI

16 

Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E and Forster R: CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood. 115:1906–1912. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Zlotoff DA, Sambandam A, Logan TD, Bell JJ, Schwarz BA and Bhandoola A: CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood. 115:1897–1905. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Liu C, Saito F, Liu Z, Lei Y, Uehara S, Love P, Lipp M, Kondo S, Manley N and Takahama Y: Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood. 108:2531–2539. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Uehara S, Grinberg A, Farber JM and Love PE: A role for CCR9 in T lymphocyte development and migration. J Immunol. 168:2811–2819. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Evans-Marin HL, Cao AT, Yao S, Chen F, He C, Liu H, Wu W, Gonzalez MG, Dann SM and Cong Y: Unexpected regulatory role of CCR9 in regulatory T cell development. PLoS One. 10:e01341002015. View Article : Google Scholar : PubMed/NCBI

21 

McGuire HM, Vogelzang A, Ma CS, Hughes WE, Silveira PA, Tangye SG, Christ D, Fulcher D, Falcone M and King C: A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity. Immunity. 34:602–615. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Tubo NJ, Wurbel MA, Charvat TT, Schall TJ, Walters MJ and Campbell JJ: A systemically-administered small molecule antagonist of CCR9 acts as a tissue-selective inhibitor of lymphocyte trafficking. PLoS One. 7:e504982012. View Article : Google Scholar : PubMed/NCBI

23 

Greis C, Rasuly Z, Janosi RA, Kordelas L, Beelen DW and Liebregts T: Intestinal T lymphocyte homing is associated with gastric emptying and epithelial barrier function in critically ill: A prospective observational study. Crit Care. 21:702017. View Article : Google Scholar : PubMed/NCBI

24 

Drakes ML, Stiff PJ and Blanchard TG: Inverse relationship between dendritic cell CCR9 expression and maturation state. Immunology. 127:466–476. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Stock A, Booth S and Cerundolo V: Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans. J Exp Med. 208:761–773. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Bakdash G, Vogelpoel LT, van Capel TM, Kapsenberg ML and de Jong EC: Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. Mucosal Immunol. 8:265–278. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Chen X, Dodge J, Komorowski R and Drobyski WR: A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease. Blood. 121:3970–3980. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Duurland CL, Brown CC, O'Shaughnessy RF and Wedderburn LR: CD161+Tconv and CD161+Treg share a transcriptional and functional phenotype despite limited overlap in TCRβ repertoire. Front Immunol. 8:1032017. View Article : Google Scholar : PubMed/NCBI

29 

Aoyama K, Saha A, Tolar J, Riddle MJ, Veenstra RG, Taylor PA, Blomhoff R, Panoskaltsis-Mortari A, Klebanoff CA, Socié G, et al: Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood. 122:2125–2134. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Wurbel MA, Malissen M, Guy-Grand D, Meffre E, Nussenzweig MC, Richelme M, Carrier A and Malissen B: Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood. 98:2626–2632. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Demberg T, Mohanram V, Venzon D and Robert-Guroff M: Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV rhesus macaque model. Clin Immunol. 153:264–276. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Ehlin-Henriksson B, Liang W, Cagigi A, Mowafi F, Klein G and Nilsson A: Changes in chemokines and chemokine receptor expression on tonsillar B cells upon Epstein-Barr virus infection. Immunology. 127:549–557. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Mizukami T, Kanai T, Mikami Y, Hayashi A, Doi T, Handa T, Matsumoto A, Jun L, Matsuoka K, Sato T, et al: CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis. Immunol Lett. 147:75–79. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Chu PS, Nakamoto N, Ebinuma H, Usui S, Saeki K, Matsumoto A, Mikami Y, Sugiyama K, Tomita K, Kanai T, et al: C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology. 58:337–350. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Amiya T, Nakamoto N, Chu PS, Teratani T, Nakajima H, Fukuchi Y, Taniki N, Yamaguchi A, Shiba S, Miyake R, et al: Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis. Sci Rep. 6:351462016. View Article : Google Scholar : PubMed/NCBI

36 

Qiuping Z, Qun L, Chunsong H, Xiaolian Z, Baojun H, Mingzhen Y, Chengming L, Jinshen H, Qingping G, Kejian Z, et al: Selectively increased expression and functions of chemokine receptor CCR9 on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia. Cancer Res. 63:6469–6477. 2003.PubMed/NCBI

37 

Mirandola L, Chiriva-Internati M, Montagna D, Locatelli F, Zecca M, Ranzani M, Basile A, Locati M, Cobos E, Kast WM, et al: Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia. J Pathol. 226:713–722. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Zhou B, Leng J, Hu M, Zhang L, Wang Z, Liu D, Tong X, Yu B, Hu Y, Deng C, et al: Ezrin is a key molecule in the metastasis of MOLT4 cells induced by CCL25/CCR9. Leuk Res. 34:769–776. 2010. View Article : Google Scholar : PubMed/NCBI

39 

Zhang L, Yu B, Hu M, Wang Z, Liu D, Tong X, Leng J, Zhou B, Hu Y, Wu R, et al: Role of Rho-ROCK signaling in MOLT4 cells metastasis induced by CCL25. Leuk Res. 35:103–109. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Nagakubo D, Jin Z, Hieshima K, Nakayama T, Shirakawa AK, Tanaka Y, Hasegawa H, Hayashi T, Tsukasaki K, Yamada Y and Yoshie O: Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax. Int J Cancer. 120:1591–1597. 2007. View Article : Google Scholar : PubMed/NCBI

41 

Annels NE, Willemze AJ, van der Velden VH, Faaij CM, van Wering E, Sie-Go DM, Egeler RM, van Tol MJ and Révész T: Possible link between unique chemokine and homing receptor expression at diagnosis and relapse location in a patient with childhood T-ALL. Blood. 103:2806–2808. 2004. View Article : Google Scholar : PubMed/NCBI

42 

Qiuping Z, Jei X, Youxin J, Wei J, Chun L, Jin W, Qun W, Yan L, Chunsong H, Mingzhen Y, et al: CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation. Cancer Res. 64:7579–7587. 2004. View Article : Google Scholar : PubMed/NCBI

43 

Deutsch AJ, Steinbauer E, Hofmann NA, Strunk D, Gerlza T, Beham-Schmid C, Schaider H and Neumeister P: Chemokine receptors in gastric MALT lymphoma: Loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma. Mod Pathol. 26:182–194. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Badr G, Lefevre EA and Mohany M: Thymoquinone inhibits the CXCL12-induced chemotaxis of multiple myeloma cells and increases their susceptibility to Fas-mediated apoptosis. PLoS One. 6:e237412011. View Article : Google Scholar : PubMed/NCBI

45 

Letsch A, Keilholz U, Schadendorf D, Assfalg G, Asemissen AM, Thiel E and Scheibenbogen C: Functional CCR9 expression is associated with small intestinal metastasis. J Invest Dermatol. 122:685–690. 2004. View Article : Google Scholar : PubMed/NCBI

46 

Seidl H, Richtig E, Tilz H, Stefan M, Schmidbauer U, Asslaber M, Zatloukal K, Herlyn M and Schaider H: Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma. Hum Pathol. 38:768–780. 2007. View Article : Google Scholar : PubMed/NCBI

47 

Amersi FF, Terando AM, Goto Y, Scolyer RA, Thompson JF, Tran AN, Faries MB, Morton DL and Hoon DS: Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin Cancer Res. 14:638–645. 2008. View Article : Google Scholar : PubMed/NCBI

48 

Richmond A: CCR9 homes metastatic melanoma cells to the small bowel. Clin Cancer Res. 14:621–623. 2008. View Article : Google Scholar : PubMed/NCBI

49 

Salerno EP, Olson WC, McSkimming C, Shea S and Slingluff CL Jr: T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins. Int J Cancer. 134:563–574. 2014. View Article : Google Scholar : PubMed/NCBI

50 

Jacquelot N, Enot DP, Flament C, Vimond N, Blattner C, Pitt JM, Yamazaki T, Roberti MP, Daillère R, Vétizou M, et al: Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma. J Clin Invest. 126:921–937. 2016. View Article : Google Scholar : PubMed/NCBI

51 

Park J, Ostrowitz MB, Cohen MS and Al-Kasspooles M: A patient with metastatic melanoma of the small bowel. Oncology (Williston Park). 23:98–102. 2009.PubMed/NCBI

52 

Fusi A, Liu Z, Kümmerlen V, Nonnemacher A, Jeske J and Keilholz U: Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J Transl Med. 10:522012. View Article : Google Scholar : PubMed/NCBI

53 

Kühnelt-Leddihn L, Müller H, Eisendle K, Zelger B and Weinlich G: Overexpression of the chemokine receptors CXCR4, CCR7, CCR9, and CCR10 in human primary cutaneous melanoma: A potential prognostic value for CCR7 and CCR10? Arch Dermatol Res. 304:185–193. 2012. View Article : Google Scholar : PubMed/NCBI

54 

Singh R, Stockard CR, Grizzle WE, Lillard JW Jr and Singh S: Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer. Int J Oncol. 39:373–381. 2011.PubMed/NCBI

55 

Johnson EL, Singh R, Singh S, Johnson-Holiday CM, Grizzle WE, Partridge EE and Lillard JW Jr: CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion. World J Surg Oncol. 8:622010. View Article : Google Scholar : PubMed/NCBI

56 

Johnson-Holiday C, Singh R, Johnson E, Singh S, Stockard CR, Grizzle WE and Lillard JW Jr: CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. Int J Oncol. 38:1279–1285. 2011.PubMed/NCBI

57 

Feng LY, Ou ZL, Wu FY, Shen ZZ and Shao ZM: Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival. Clin Cancer Res. 15:2962–2970. 2009. View Article : Google Scholar : PubMed/NCBI

58 

Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI

59 

Johnson-Holiday C, Singh R, Johnson EL, Grizzle WE, Lillard JW Jr..Singh S: CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion. World J Surg Oncol. 9:462011. View Article : Google Scholar : PubMed/NCBI

60 

Singh S, Singh UP, Stiles JK, Grizzle WE and Lillard JW Jr: Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clin Cancer Res. 10:8743–8750. 2004. View Article : Google Scholar : PubMed/NCBI

61 

Sharma PK, Singh R, Novakovic KR, Eaton JW, Grizzle WE and Singh S: CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. Int J Cancer. 127:2020–2030. 2010. View Article : Google Scholar : PubMed/NCBI

62 

Shen X, Mailey B, Ellenhorn JD, Chu PG, Lowy AM and Kim J: CC chemokine receptor 9 enhances proliferation in pancreatic intraepithelial neoplasia and pancreatic cancer cells. J Gastrointest Surg. 13:1955–1962. 2009. View Article : Google Scholar : PubMed/NCBI

63 

Heinrich EL, Arrington AK, Ko ME, Luu C, Lee W, Lu J and Kim J: paracrine activation of chemokine receptor CCR9 enhances the invasiveness of pancreatic cancer cells. Cancer Microenviron. 6:241–245. 2013. View Article : Google Scholar : PubMed/NCBI

64 

Chen HJ, Sun J, Huang Z, Hou H Jr, Arcilla M, Rakhilin N, Joe DJ, Choi J, Gadamsetty P, Milsom J, et al: Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting. Nat Biotechnol. 33:656–660. 2015. View Article : Google Scholar : PubMed/NCBI

65 

Zhang Z, Sun T, Chen Y, Gong S, Sun X, Zou F and Peng R: CCL25/CCR9 Signal promotes migration and invasion in hepatocellular and breast cancer cell lines. DNA Cell Biol. 35:348–357. 2016. View Article : Google Scholar : PubMed/NCBI

66 

Zhang Z, Qin C, Wu Y, Su Z, Xian G and Hu B: CCR9 as a prognostic marker and therapeutic target in hepatocellular carcinoma. Oncol Rep. 31:1629–1636. 2014. View Article : Google Scholar : PubMed/NCBI

67 

Zhong Y, Jiang L, Lin H, Li B, Lan J, Liang S, Shen B, Lei Z and Zheng W: Expression of CC chemokine receptor 9 predicts poor prognosis in patients with lung adenocarcinoma. Diagn Pathol. 10:1012015. View Article : Google Scholar : PubMed/NCBI

68 

Gupta P, Sharma PK, Mir H, Singh R, Singh N, Kloecker GH, Lillard JW Jr and Singh S: CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis. Oncotarget. 5:10170–10179. 2014. View Article : Google Scholar : PubMed/NCBI

69 

Mishan MA, Heirani-Tabasi A, Mokhberian N, Hassanzade M, Kalalian Moghaddam H, Bahrami AR and Ahmadiankia N: Analysis of chemokine receptor gene expression in esophageal cancer cells compared with breast cancer with insights into metastasis. Iran J Public Health. 44:1353–1358. 2015.PubMed/NCBI

70 

Chamorro S, Vela M, Franco-Villanueva A, Carramolino L, Gutiérrez J, Gómez L, Lozano M, Salvador B, García-Gallo M, Martínez-A C and Kremer L: Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts. MAbs. 6:1000–1012. 2014. View Article : Google Scholar : PubMed/NCBI

71 

Khandelwal N, Breinig M, Speck T, Michels T, Kreutzer C, Sorrentino A, Sharma AK, Umansky L, Conrad H, Poschke I, et al: A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes. EMBO Mol Med. 7:450–463. 2015. View Article : Google Scholar : PubMed/NCBI

72 

Hu Y, Zhang L, Wu R, Han R, Jia Y, Jiang Z, Cheng M, Gan J, Tao X and Zhang Q: Specific killing of CCR9 high-expressing acute T lymphocytic leukemia cells by CCL25 fused with PE38 toxin. Leuk Res. 35:1254–1260. 2011. View Article : Google Scholar : PubMed/NCBI

73 

Youn BS, Kim YJ, Mantel C, Yu KY and Broxmeyer HE: Blocking of c-FLIP(L)-independent cycloheximide-induced apoptosis or Fas-mediated apoptosis by the CC chemokine receptor 9/TECK interaction. Blood. 98:925–933. 2001. View Article : Google Scholar : PubMed/NCBI

74 

Deng X, Tu Z, Xiong M, Tembo K, Zhou L, Liu P, Pan S, Xiong J, Yang X, Leng J, et al: Wnt5a and CCL25 promote adult T-cell acute lymphoblastic leukemia cell migration, invasion and metastasis. Oncotarget. 8:39033–39047. 2017.PubMed/NCBI

75 

Shang L, Thirunarayanan N, Viejo-Borbolla A, Martin AP, Bogunovic M, Marchesi F, Unkeless JC, Ho Y, Furtado GC, Alcami A, et al: Expression of the chemokine binding protein M3 promotes marked changes in the accumulation of specific leukocytes subsets within the intestine. Gastroenterology. 137:1006–1018, 1018.e1-3. 2009. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August-2018
Volume 16 Issue 2

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang C, Liu Z, Xu Z, Wu X, Zhang D, Zhang Z and Wei J: The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review). Oncol Lett 16: 2071-2077, 2018.
APA
Wang, C., Liu, Z., Xu, Z., Wu, X., Zhang, D., Zhang, Z., & Wei, J. (2018). The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review). Oncology Letters, 16, 2071-2077. https://doi.org/10.3892/ol.2018.8896
MLA
Wang, C., Liu, Z., Xu, Z., Wu, X., Zhang, D., Zhang, Z., Wei, J."The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review)". Oncology Letters 16.2 (2018): 2071-2077.
Chicago
Wang, C., Liu, Z., Xu, Z., Wu, X., Zhang, D., Zhang, Z., Wei, J."The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review)". Oncology Letters 16, no. 2 (2018): 2071-2077. https://doi.org/10.3892/ol.2018.8896