Abstract
Background and objectives
CXCR4 and its ligand, SDF-1α, play an important role in the targeted metastasis of colon cancer. In this study, we analyzed an expression of CXCR4 in clinical samples and showed that SDF-1α affected the expression of CXCR4 in colon cancer cells.
Materials and methods
A total of 388 patients with colorectal cancer (CRC) who underwent surgery in Taipei Veterans General Hospital from 2000 to 2004 were included. The expression of CXCR4 in CRC was visualized by immunohistochemistry (anti-CXCR4 mAb, R&D 12G5). HCT116, SW480, and SW620 cells were treated with SDF-1α in vitro and the CXCR4 proteins located in the cytoplasmic and nuclear compartments were separated and analyzed with western blotting.
Results
The frequency of cytoplasmic and nuclear expression of CXCR4 in colorectal cancers was 35.6% and 36.9%, respectively. Nuclear but not cytoplasmic expression of CXCR4 was associated with advanced CRC (p < 0.001) and lymphovascular invasion. However, in multivariate analysis, nuclear expression of CXCR4 did not correlate with patients' outcome. In the in vitro study, SDF-1α, stimulation of three colorectal carcinoma lines enhanced the CXCR4 nuclear expression.
Conclusion
Expression of the CXCR4 plays a role in CRC progression and may be associated with SDF-1α stimulation.
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Abbreviations
- CRC:
-
Colorectal cancer
- DFS:
-
Disease-free survival
References
The Department of Health, Executive Yuan (2007) Cancer registry annual report. R.O.C., Taiwan
Stetler-Stevenson WG, Kleiner DeVita VT, Hellman S, Rosenberg SA (2001) Molecular biology of cancer: invasion and metastasis. Principles and Practice of Oncology. Lippincott Williams & Wilkins, Philadelphia, pp 123–136
Taichman RS, Cooper C, Keller ET et al (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62:1832–1837
Scotton CJ, Wilson JL, Milliken D et al (2001) Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res 61:4961–4965
Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56
Koshiba T, Hosotani R, Miyamoto Y et al (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression. Clin Cancer Res 6:3530–3535
Ben-Baruch A (2003) Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res 5:31–36
Kato M, Kitayama J, Kazama S, Nagawa H (2003) Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 5:R144–R150
Kollmar O, Rupertus K, Scheuer C et al (2007) Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis. Neoplasia 9:862–870
Guleng B, Tateishi K, Ohta M et al (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 65:5864–5871
Zeelenberg IS, Ruuls-Van Stalle L, Roos E (2003) The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res 63:3833–3839
Salvucci O, Bouchard A, Baccarelli A et al (2006) The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study. Breast Cancer Res Treat 97:275–283
Lin SY, Makino K, Xia W et al (2001) Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 3:802–808
Ueda Y, Neel NF, Schutyser E et al (2006) Deletion of the COOH-terminal domain of CXC chemokine receptor 4 leads to the down-regulation of cell-to-cell contact, enhanced motility and proliferation in breast carcinoma cells. Cancer Res 66:5665–5675
Diaz GA (2005) CXCR4 mutations in WHIM syndrome: a misguided immune system? Immunol Rev 203:235–243
Wittekind C, Greene FL, Henson DE et al (2003) TNM supplement: a commentary on uniform use, 3rd edn. Wiley, New York, pp 97–123
Shim H, Lau SK, Devi S et al (2006) Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha. Biochem Biophys Res Commun 346:252–258
Lo HW, Xia W, Wei Y et al (2005) Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res 65:338–348
Geminder H, Sagi-Assif O, Goldberg L et al (2001) A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone metastasis in neuroblastoma. J Immunol 167:4747–4757
Mohle R, Failenschmid C, Bautz F, Kanz L (1999) Overexpression of chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to SDF-1. Leukemia 13:1954–1959
Tarasova NI, Stauber RH, Michejda CJ (1998) Spontaneous and ligand induced trafficking of CXC-chemokine receptor 4. J Biol Chem 273:15883–15886
Wang N, Wu QL, Fang Y et al (2005) Expression of chemokine receptor CXCR4 in nasopharyngeal carcinoma: pattern of expression and correlation with clinical outcome. J Transl Med 3:26–30
Spano JP, Andre F, Morat L et al (2004) Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol 15:613–617
Shibuta K, Mori M, Shimoda K, Inoue H, Mitra P (2002) Barnard GF.Regional expression of CXCL12/CXCR4 in liver and hepatocellular carcinoma and cell-cycle variation during in vitro differentiation. Jpn J Cancer Res 93:789–797
Yoshitake N, Fukui YH, Sekikawa A, Fujii S, Tomita S, Ichikawa K, Imura J, Hiraishi H, Fujimori T (2008) Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer 98:1682–1689
Haribabu B, Richardson RM, Fisher I, Sozzani S, Peiper SC, Horuk R, Ali H, Snyderman R (1997) Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem 272:28726–28731
Kucia M, Reca R, Miekus K et al (2005) Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23:879–894
Kim J, Takeuchi H, Lam ST, Turner RR, Wang HJ, Kuo C, Foshag L, Bilchik AJ, Hoon DS (2005) Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol 23:2744–2753
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
Chang SC, Lin PC, Yang SH et al (2009) SDF-1alpha G801A polymorphism predicts lymph node metastasis in stage T3 colorectal cancer. Ann Surg Oncol 16:2323–2330
Lapteva N, Yang AG, Sanders DE et al (2005) CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo. Cancer Gene Ther 12:84–89
Smith MC, Luker KE, Garbow JR et al (2004) CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 64:8604–8612
Rubin JB, Kung AL, Klein RS et al (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 100:13513–13518
Dommange F, Cartron G, Espanel C et al (2006) CXCL12 polymorphism and malignant cell dissemination/tissue infiltration in acute myeloid leukemia. FASEB J 20:1913–1915
Acknowledgement
This study was supported by the grants from Taipei-Veterans General Hospital (V99C1-011, V99A-015, V98C1-093).
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Supplementary Table
Staged 5-year survival rate (95% confidence interval) of 388 CRC patients in relation to cytoplasmic or nuclear CXCR4 status (DOC 24 kb)
Supplementary Fig. 1
(GIF 131 kb)
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Wang, SC., Lin, JK., Wang, HS. et al. Nuclear expression of CXCR4 is associated with advanced colorectal cancer. Int J Colorectal Dis 25, 1185–1191 (2010). https://doi.org/10.1007/s00384-010-0999-1
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DOI: https://doi.org/10.1007/s00384-010-0999-1