Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model

Kee,Ji-Ye; Ito,Aya; Hojo,Shozo; Hashimoto,Isaya; Igarashi,Yoshiko; Tsukada,Kazuhiro; Irimura,Tatsuro; Shibahara,Naotoshi; Nakayama,Takashi; Yoshie,Osamu; Sakurai,Hiroaki; Saiki,Ikuo; Koizumi,Keiichi

doi:10.3892/or.2012.2185

Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model

Authors:
- Ji-Ye Kee
- Aya Ito
- Shozo Hojo
- Isaya Hashimoto
- Yoshiko Igarashi
- Kazuhiro Tsukada
- Tatsuro Irimura
- Naotoshi Shibahara
- Takashi Nakayama
- Osamu Yoshie
- Hiroaki Sakurai
- Ikuo Saiki
- Keiichi Koizumi
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Affiliations: Division of Pathogenic Biochemistry, University of Toyama, Toyama 930-0194, Japan, Department of Surgery (II), Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan, Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan, Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan, Division of Chemotherapy, Kinki University School of Pharmaceutical Sciences, Osaka 577-8502, Japan, Department of Microbiology, Kinki University School of Medicine, Osaka 589-8511, Japan, Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
Published online on: December 13, 2012 https://doi.org/10.3892/or.2012.2185
Pages: 975-982

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Abstract

Colorectal cancer (CRC) is a typical lifestyle-related disease, and it metastasizes mostly to the liver. It is important to understand the molecular mechanisms of CRC metastasis in order to design new and effective treatments for CRC patients. Chemokines are known to have antitumor effects as their chemoattractant properties stimulate the accumulation of infiltrating immune cells (TILs) in tumors. Chemokine (C-X-C motif) ligand 16 (CXCL16), also known as SR-PSOX, is a unique membrane-bound chemokine that induces the expression of its specific receptor CXCR6. We previously reported that the expression of CXCL16 by cancer cells enhances the recruitment of TILs, thereby improving the prognosis of CRC. It has since been reported that CXCL16/CXCR6 expression is involved in the metastasis of various types of cancer. However, there is no report of the association between CXCL16 expression and liver metastasis in CRC. In this study, we investigated the role of cancer-derived CXCL16 and the possibility of gene therapy using CXCL16. Therefore, we examined the metastasis of colon 38 SL4 cells to the liver in an experimental model. Following injection of cancer cells into the intraportal vein, CXCL16-expressing CRC cells drastically inhibited liver metastasis. We also found that CD8 T cells and natural killer T (NKT) cells, known as CXCR6-expressing cells, increased in CXCL16-expressing metastatic tissue. Collectively, the inhibitory effect on metastasis to the liver by CXCL16 was observed in NKT cell-depleted mice but not in CD8 T cell-depleted mice. These results demonstrate the inhibitory effect of CXCL16 on liver metastasis via NKT cells in CRC.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA and Lu D: Local surgical, ablative, and radiation treatment of metastases. CA Cancer J Clin. 59:145–170. 2009. View Article : Google Scholar : PubMed/NCBI
3	Zlotnik A, Burkhardt AM and Homey B: Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol. 11:597–606. 2011. View Article : Google Scholar : PubMed/NCBI
4	Koizumi K, Hojo S, Akashi T, Yasumoto K and Saiki I: Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci. 98:1652–1658. 2007. View Article : Google Scholar : PubMed/NCBI
5	Koizumi K, Kato S, Sakurai H, Hashimoto I, Yasumoto K and Saiki I: Therapeutics target of CXCR4 and its downstream in peritoneal carcinomatosis of gastric cancer. Front Biosci (Schol Ed). 4:269–276. 2012. View Article : Google Scholar : PubMed/NCBI
6	Matloubian M, David A, Engel S, Ryan JE and Cyster JG: A transmembrane CXC chemokine is a ligand for HIV coreceptor Bonzo. Nat Immunol. 1:298–304. 2000. View Article : Google Scholar : PubMed/NCBI
7	Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T and Yonehara S: Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem. 275:40663–40666. 2000. View Article : Google Scholar : PubMed/NCBI
8	Wilbanks A, Zondlo SC, Murphy K, Mak S, Soler D, Langdon P, Andrew DP, Wu L and Briskin M: Expression cloning of the STRL33/BONZO/TYMSTR ligand reveals elements of CC, CXC, and CX3C chemokines. J Immunol. 166:5145–5154. 2001. View Article : Google Scholar : PubMed/NCBI
9	Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Sedlacek R, Dietrich S, Muetze B, Schuster B, Kallen KJ, Saftig P, Rose-John S and Ludwig A: The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol. 172:6362–6372. 2004. View Article : Google Scholar : PubMed/NCBI
10	Gough PJ, Garton KJ, Wille PT, Rychlewski M, Dempsey PJ and Raines EW: A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16. J Immunol. 172:3678–3685. 2004. View Article : Google Scholar : PubMed/NCBI
11	Ludwig A, Hundhausen C, Lambert MH, Broadway N, Andrews RC, Bickett DM, Leesnitzer MA and Becherer JD: Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen. 8:161–171. 2005. View Article : Google Scholar
12	Gutwein P, Schramme A, Sinke N, Abdel-Bakky MS, Voss B, Obermuller N, Doberstein K, Koziolek M, Fritzsche F, Johannsen M, Jung K, Schaider H, Altevogt P, Ludwig A, Pfeilschifter J and Kristiansen G: Tumoural CXCL16 expression is a novel prognostic marker of longer survival times in renal cell cancer patients. Eur J Cancer. 10:1016–1023. 2008.PubMed/NCBI
13	Lu Y, Wang J, Xu Y, Koch AE, Cai Z, Chen X, Galson DL, Taichman RS and Zhang J: CXCL16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol Cancer Res. 6:546–554. 2008. View Article : Google Scholar : PubMed/NCBI
14	Darash-Yahana M, Gillespie JW, Hewitt SM, Chen YY, Maeda S, Stein I, Singh SP, Bedolla RB, Peled A, Troyer DA, Pikarsky E, Karin M and Farber JM: The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. Plos One. 4:e66952009. View Article : Google Scholar : PubMed/NCBI
15	Hojo S, Koizumi K, Tsuneyama K, Arita Y, Cui Z, Shinohara K, Minami T, Hashimoto I, Nakayama T, Sakurai H, Takano Y, Yoshie O, Tsukada K and Saiki I: High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res. 67:4725–4731. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wågsäter D, Hugander A and Dimberg J: Expression of CXCL16 in human rectal cancer. Int J Mol Med. 14:65–69. 2004.
17	Wente MN, Gaida MM, Mayer C, Michalski CW, Haag N, Giese T, Felix K, Bergmann F, Giese NA and Friess H: Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int J Oncol. 33:297–308. 2008.PubMed/NCBI
18	Ou DL, Chen CL, Lin SB, Hsu CH and Lin LI: Chemokine receptor expression profiles in nasopharyngeal carcinoma and their association with metastasis and radiotherapy. J Pathol. 210:363–373. 2006. View Article : Google Scholar : PubMed/NCBI
19	Held-Feindt J, Rehmke B, Mentlein R, Hattermann K, Knerlich F, Hugo HH, Ludwig A and Mehdorn HM: Overexpression of CXCL16 and its receptor CXCR6/Bonzo promotes growth of human schwannomas. Glia. 56:764–774. 2008. View Article : Google Scholar : PubMed/NCBI
20	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. Human Pathol. 38:768–780. 2007. View Article : Google Scholar : PubMed/NCBI
21	Kim CH, Kunkel EJ, Boisvert J, Johnston B, Campbell JJ, Genovese MC, Greenberg HB and Butcher EC: Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest. 107:595–601. 2001. View Article : Google Scholar : PubMed/NCBI
22	Kim CH, Johnston B and Butcher EC: Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity. Blood. 100:11–16. 2002.PubMed/NCBI
23	Taniguchi M, Harada M, Kojo S, Nakayama T and Wakao H: The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol. 21:483–513. 2003. View Article : Google Scholar : PubMed/NCBI
24	Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kanno M and Taniguchi M: Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science. 278:1623–1626. 1997. View Article : Google Scholar : PubMed/NCBI
25	Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Sato H, Kondo E, Harada M, Koseki H, Nakayama T, Tanaka Y and Taniguchi M: Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc Natl Acad Sci USA. 95:5690–5693. 1998. View Article : Google Scholar : PubMed/NCBI
26	Toura I, Kawano T, Akutsu Y, Nakayama T, Ochiai T and Taniguchi M: Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with alpha-galactosylceramide. J Immunol. 163:2387–2391. 1999.PubMed/NCBI
27	Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY and Godfrey DI: Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 191:661–668. 2000. View Article : Google Scholar : PubMed/NCBI
28	Cullen R, Germanov E, Shimaoka T and Johnston B: Enhanced tumor metastasis in response to blockade of the chemokine receptor CXCR6 is overcome by NKT cell activation. J Immunol. 183:5807–5815. 2009. View Article : Google Scholar : PubMed/NCBI
29	Nakagawa R, Nagafune I, Tazunoki Y, Ehara H, Tomura H, Iijima R, Motoki K, Kamishohara M and Seki S: Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by alpha-galactosylceramide in mice. J Immunol. 166:6578–6584. 2001. View Article : Google Scholar : PubMed/NCBI
30	Smyth MJ, Crowe NY, Pellicci DG, Kyparissoudis K, Kelly JM, Takeda K, Yagita H and Godfrey DI: Sequential production of interferon-gamma by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of alpha-galactosylceramide. Blood. 99:1259–1266. 2002.
31	Tachibana T, Onodera H, Tsuruyama T, Mori A, Nagayama S, Hiai H and Imamura M: Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res. 11:7322–7327. 2005. View Article : Google Scholar
32	Thomas SY, Hou R, Boyson JE, Means TK, Hess C, Olson DP, Strominger JL, Brenner MB, Gumperz JE, Wilson SB and Luster AD: CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J Immunol. 171:2571–2580. 2003. View Article : Google Scholar : PubMed/NCBI
33	Johnston B, Kim CH, Soler D, Emoto M and Butcher EC: Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol. 171:2960–2969. 2003. View Article : Google Scholar : PubMed/NCBI
34	Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML and Littman DR: Intravascular immune surveillance by CXCR6⁺ NKT cells patrolling liver sinusoids. PLoS Biol. 3:e1132005. View Article : Google Scholar : PubMed/NCBI
35	Germanov E, Veinotte L, Cullen R, Chamberlain E, Butcher EC and Johnston B: Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells. J Immunol. 181:81–91. 2008. View Article : Google Scholar : PubMed/NCBI
36	Ha HK, Lee W, Park HJ, Lee SD, Lee JZ and Chung MK: Clinical significance of CXCL16/CXCR6 expression in patients with prostate cancer. Mol Med Rep. 4:419–424. 2011.PubMed/NCBI
37	Guo L, Cui ZM, Zhang J and Huang Y: Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin J Cancer. 30:336–343. 2011. View Article : Google Scholar : PubMed/NCBI
38	Lombardi V, Stock P, Singh AK, Kerzerho J, Yang W, Sullivan BA, Li X, Shiratsuchi T, Hnatiuk NE, Howell AR, Yu KO, Porcelli SA, Tsuji M, Kronenberg M, Wilson SB and Akbari O: A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity. J Immunol. 184:2107–2115. 2010. View Article : Google Scholar : PubMed/NCBI
39	Sato T, Thorlacius H, Johnston B, Staton TL, Xiang W, Littman DR and Butcher EC: Role for CXCR6 in recruitment of activated CD8⁺ lymphocytes to inflamed liver. J Immunol. 174:277–283. 2005. View Article : Google Scholar : PubMed/NCBI
40	Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M and Adams DH: CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol. 174:1055–1062. 2005. View Article : Google Scholar
41	Wang RF: CD8⁺ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol. 69:811–814. 2008.
42	Slettenaar VI and Wilson JL: The chemokine network: a target in cancer biology? Adv Drug Deliv Rev. 58:962–974. 2006. View Article : Google Scholar : PubMed/NCBI