Top

Published in:

01-07-2012 | Translational Research and Biomarkers

Soluble CXCL16 in Preoperative Serum is a Novel Prognostic Marker and Predicts Recurrence of Liver Metastases in Colorectal Cancer Patients

Authors: Kohei Matsushita, Yuji Toiyama, Koji Tanaka, Susumu Saigusa, Junichiro Hiro, Keiichi Uchida, Yasuhiro Inoue, Masato Kusunoki

Published in: Annals of Surgical Oncology | Special Issue 3/2012

Abstract

Purpose

This study was designed to identify novel and reliable serum prognostic markers in patients with colorectal cancer (CRC).

Methods

Based on cytokine array analysis, we identified soluble CXCL16 as a novel prognostic serum marker. Serum levels of CXCL16 were assessed in 314 CRC patients and 20 normal volunteers by enzyme-linked immunosorbent assay, and their relationships with clinicopathologic findings, including survival, were investigated. Proliferation, invasion, and wound healing assays were used to investigate the biological role of soluble CXCL16 in CRC cells, by exposure of HT-29 cells to recombinant CXCL16.

Results

The median serum CXCL16 concentration in CRC patients was significantly higher than that in normal volunteers. In addition, serum CXCL16 levels increased significantly in accordance with the progression of UICC stage classification. Elevated serum CXCL16 level was significantly associated with poor survival and was an independent prognostic marker in CRC patients. Furthermore, in stage I–III CRC patients who underwent curative intent surgery, elevated serum CXCL16 levels were significantly associated with metachronous liver recurrence and poor survival. Recombinant soluble CXCL16 promoted the epithelial–mesenchymal transition (EMT) phenotype characterized by impaired E-cadherin production and induction of vimentin in vitro. In addition, recombinant soluble CXCL16 promoted cell growth, migration, and invasion in a CRC cell line.

Conclusions

In this study, we identified CXCL16 as a novel prognostic marker. Preoperative high serum levels of CXCL16 were associated with metachronous liver recurrence and poor prognosis in CRC patients. Soluble CXCL16 may play an important role in liver metastases through the induction of EMT.

Messerini L, Cianchi F, Cortesini C, Comin CE. Incidence and prognostic significance of occult tumor cells in lymph nodes from patients with stage IIA colorectal carcinoma. Hum Pathol. 2006;37(10):1259–67.PubMedCrossRef

Shih W, Chetty R, Tsao MS. Expression profiling by microarrays in colorectal cancer (Review). Oncol Rep. 2005;13(3):517–24.PubMed

Andre N, Schmiegel W. Chemoradiotherapy for colorectal cancer. Gut. 2005;54(8):1194–202.PubMedCrossRef

Lurje G, Zhang W, Lenz HJ. Molecular prognostic markers in locally advanced colon cancer. Clin Colorectal Cancer. 2007;6(10):683–90.PubMedCrossRef

Halama N, Herrmann C, Jaeger D, Herrmann T. Treatment with cetuximab, bevacizumab and irinotecan in heavily pretreated patients with metastasized colorectal cancer. Anticancer Res. 2008; 28(6B):4111–5.PubMed

Yoshie O, Imai T, Nomiyama H. Chemokines in immunity. Adv Immunol. 2001;78:57–110.PubMedCrossRef

Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastases. Nature. 2001;410(6824):50–6.PubMedCrossRef

Yasumoto K, Koizumi K, Kawashima A, et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 2006;66(4):2181–7.PubMedCrossRef

Nakamura ES, Koizumi K, Kobayashi M, et al. RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastases of lung cancer expressing its receptor CCR4. Clin Exp Metastases. 2006;23(1):9–18.CrossRef

10.

Bates RC, DeLeo MJ 3rd, Mercurio AM. The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis. Exp Cell Res. 2004;299(2):315–24.PubMedCrossRef

11.

Lu Y, Wang J, Xu Y, et al. CXCL16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol Cancer Res. 2008;6(4):546–54.PubMedCrossRef

12.

Wang J, Lu Y, Koch AE, et al. CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. Cancer Res. 2008;68(24):10367–76.PubMedCrossRef

13.

Gutwein P, Schramme A, Sinke N, et al. Tumoural CXCL16 expression is a novel prognostic marker of longer survival times in renal cell cancer patients. Eur J Cancer. 2009;45(3):478–89.PubMedCrossRef

14.

Ou DL, Chen CL, Lin SB, et al. Chemokine receptor expression profiles in nasopharyngeal carcinoma and their association with metastases and radiotherapy. J Pathol. 2006;210(3):363–73.PubMedCrossRef

15.

Seidl H, Richtig E, Tilz H, et al. Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma. Hum Pathol. 2007;38(5):768–80.PubMedCrossRef

16.

Huang L, Zhao A, Wong F, et al. Leukotriene B4 strongly increases monocyte chemoattractant protein-1 in human monocytes. Arterioscler Thromb Vasc Biol. 2004;24(10):1783–8.PubMedCrossRef

17.

Wu Q, Esuvaranathan K, Mahendran R. Monitoring the response of orthotopic bladder tumors to granulocyte macrophage colony-stimulating factor therapy using the prostate-specific antigen gene as a reporter. Clin Cancer Res. 2004;10(20):6977–84.PubMedCrossRef

18.

Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.PubMedCrossRef

19.

Zhou Q, Desta T, Fenton M, et al. Cytokine profiling of macrophages exposed to Porphyromonas gingivalis, its lipopolysaccharide, or its FimA protein. Infect Immun. 2005;73(2):935–43.PubMedCrossRef

20.

Saigusa S, Toiyama Y, Tanaka K, et al. Stromal CXCR4 and CXCL12 expression is associated with distant recurrence and poor prognosis in rectal cancer after chemoradiotherapy. Ann Surg Oncol. 2010;17(8):2051–8.PubMedCrossRef

21.

Toiyama Y, Inoue Y, Yasuda H, et al. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness. J Gastroenterol. doi:10.1007/s00535-010-0318-1.

22.

Yokoe T, Toiyama Y, Okugawa Y, et al. KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Ann Surg Oncol. 2010;17(3):821–8.PubMedCrossRef

23.

Matloubian M, David A, Engel S, et al. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol. 2000;1(4):298–304.PubMedCrossRef

24.

Abel S, Hundhausen C, Mentlein R, et al. 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. 2004;172(10):6362–72.PubMed

25.

Wilbanks A, Zondlo SC, Murphy K, et al. Expression cloning of the STRL33/BONZO/TYMSTR ligand reveals elements of CC, CXC, and CX3C chemokines. J Immunol. 2001;166(8):5145–54.PubMed

26.

Motsinger A, Haas DW, Stanic AK, et al. CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection. J Exp Med. 2002;195(7):869–79.PubMedCrossRef

27.

Kim CH, Kunkel EJ, Boisvert J, et al. Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest. 2001;107(5):595–601.PubMedCrossRef

28.

Wente MN, Gaida MM, Mayer C, et al. Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int J Oncol. 2008;33(2):297–308.PubMed

29.

Wagsater D, Hugander A, Dimberg J. Expression of CXCL16 in human rectal cancer. Int J Mol Med. 2004;14(1):65–9.PubMed

30.

Hojo S, Koizumi K, Tsuneyama K, et al. High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res. 2007;67(10):4725–31.PubMedCrossRef

31.

Leitch EF, Chakrabarti M, Crozier JE, et al. Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer. 2007;97(9):1266–70.PubMedCrossRef

32.

Sharma R, Zucknick M, London R, et al. Systemic inflammatory response predicts prognosis in patients with advanced-stage colorectal cancer. Clin Colorectal Cancer. 2008;7(5):331–7.PubMedCrossRef

33.

Onoue T, Uchida D, Begum NM, et al. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol. 2006;29(5):1133–8.PubMed

34.

Taki M, Higashikawa K, Yoneda S, et al. Up-regulation of stromal cell-derived factor-1alpha and its receptor CXCR4 expression accompanied with epithelial–mesenchymal transition in human oral squamous cell carcinoma. Oncol Rep. 2008;19(4):993–8.PubMed

35.

Bertran E, Caja L, Navarro E, et al. Role of CXCR4/SDF-1 alpha in the migratory phenotype of hepatoma cells that have undergone epithelial–mesenchymal transition in response to the transforming growth factor-beta. Cell Signal. 2009;21(11):1595–606.PubMedCrossRef

36.

Marchesi F, Piemonti L, Fedele G, et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 2008;68(21):9060–9.PubMedCrossRef

37.

Minn AJ, Gupta GP, Siegel PM, et al. Genes that mediate breast cancer metastases to lung. Nature. 2005;436(7050):518–24.PubMedCrossRef

38.

Hu W, Zhen X, Xiong B, et al. CXCR6 is expressed in human prostate cancer in vivo and is involved in the in vitro invasion of PC3 and LNCap cells. Cancer Sci. 2008;99(7):1362–9.PubMedCrossRef

39.

Ben-Baruch A. Organ selectivity in metastases: regulation by chemokines and their receptors. Clin Exp Metastases. 2008;25(4):345–56.CrossRef

Title: Soluble CXCL16 in Preoperative Serum is a Novel Prognostic Marker and Predicts Recurrence of Liver Metastases in Colorectal Cancer Patients
Authors: Kohei Matsushita
Yuji Toiyama
Koji Tanaka
Susumu Saigusa
Junichiro Hiro
Keiichi Uchida
Yasuhiro Inoue
Masato Kusunoki
Publication date: 01-07-2012
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue Special Issue 3/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-011-1993-8

At a glance: The STEP trials

Springer Medicine

Soluble CXCL16 in Preoperative Serum is a Novel Prognostic Marker and Predicts Recurrence of Liver Metastases in Colorectal Cancer Patients

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Special Issue 3/2012

A Pathway-Based Approach to Identify Molecular Biomarkers in Cancer

Recurrence and Poor Prognosis Following Resection of Small Hepatitis B-Related Hepatocellular Carcinoma Lesions Are Associated with Aberrant Tumor Expression Profiles of Glypican 3 and Osteopontin

Cortical and Subventricular Zone Glioblastoma-Derived Stem-Like Cells Display Different Molecular Profiles and Differential In Vitro and In Vivo Properties

MicroRNA-200b Regulates Cell Proliferation, Invasion, and Migration by Directly Targeting ZEB2 in Gastric Carcinoma

Clinicopathological Analysis of β-catenin and Axin-1 in Solid Pseudopapillary Neoplasms of the Pancreas

Role of the Hypoxia-Related Gene, JMJD1A, in Hepatocellular Carcinoma: Clinical Impact on Recurrence after Hepatic Resection