Skip to main content

Advertisement

Springer Nature Link
Log in

Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies

  • Research Article
  • Published:
Tumor Biology

Abstract

Chemokines have been proposed to contribute to tumour growth and metastatic spread of several cancer entities. Here, we examined the relative levels of CXCL12/CXCR4 in resection specimens from patients with different malignant and non-malignant colorectal diseases as well as colorectal liver metastases (CRLM). CXCL12/CXCR4 mRNA and protein expression profiles were assessed by quantitative real-time PCR, Western blot analysis, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry in resection specimens from patients with ulcerative colitis (UC; n = 15), colorectal adenoma (CRA; n = 15), colorectal adenocarcinoma (CRC; n = 47) and CRLM (n = 16). Corresponding non-affected tissues served as control. In contrast to UC tissues, CXCL12 showed a distinct down-regulation in CRA, CRC and CRLM specimens, whereas the corresponding receptor CXCR4 demonstrated a significant up-regulation in CRC and CRLM related to corresponding non-affected tissues (p < 0.05, respectively). Our results strongly suggest an association between CXCL12/CXCR4 expression and the induction of CRA, CRC and the development of CRLM. Therefore, CXCR4 may be a potential target for specific therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics 2007. CA Cancer J Clin. 2007;57:43–66.

    Article  PubMed  Google Scholar 

  2. Booth RA. Minimally invasive biomarkers for detection and staging of colorectal cancer. Cancer Lett. 2007;249:87–96.

    Article  CAS  PubMed  Google Scholar 

  3. McLeod HL, McKay JA, Collie-Duguid ESR, Cassidy J. Therapeutic opportunities from tumour biology in metastatic colon cancer. Eur J Cancer. 2000;36:1706–12.

    Article  CAS  PubMed  Google Scholar 

  4. Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22:6524–36.

    Article  CAS  PubMed  Google Scholar 

  5. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.

    Article  CAS  PubMed  Google Scholar 

  6. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2004;410:50–6.

    Article  Google Scholar 

  7. Schrader AJ, Lechner O, Templin M, Dittmar KE, Machtens S, Mengel M, et al. CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer. 2002;86:1250–6.

    Article  CAS  PubMed  Google Scholar 

  8. Voermans C, van Heese WP, De Jong I, Gerritsen WR, van Der Schoot CE. Migratory behavior of leukemic cells from acute myeloid leukemia patients. Leukemia. 2002;16:650–7.

    Article  CAS  PubMed  Google Scholar 

  9. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–7.

    CAS  PubMed  Google Scholar 

  10. Rubie C, Kollmar O, Frick VO, Wagner M, Brittner B, Gräber S, et al. Differential CXC receptor expression in colorectal carcinomas. Scand J Immunol. 2008;68:635–44.

    CAS  PubMed  Google Scholar 

  11. Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP. CXCR4, a chemokine receptor is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol. 1998;69:99–104.

    Article  CAS  PubMed  Google Scholar 

  12. Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsujy S, Nakajima S, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res. 2000;6:3530–5.

    CAS  PubMed  Google Scholar 

  13. Bertolini F, Dell’Agnola C, Mancuso P, Rabascio C, Burlini A, Monestiroli S, et al. CXCR4 neutralization, a novel therapeutic approach for Non-Hodgkin’s lymphoma. Cancer Res. 2002;62:3106–12.

    CAS  PubMed  Google Scholar 

  14. Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM. The stromal derived factor –1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung metastases. Am J Respir Crit Care Med. 2003;167:1667–86.

    Article  Google Scholar 

  15. Schimanski CC, Galle PR, Moehler M. Chemokine receptor CXCR4-prognostic factor for gastrointestinal tumors. World J Gastroenterol. 2008;14:4721–4.

    Article  CAS  PubMed  Google Scholar 

  16. Kim J, Takeuchi H, Lam ST, Turner RR, Wang HJ, Kuo C, et al. Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol. 2005;23:2744–53.

    Article  CAS  PubMed  Google Scholar 

  17. Wang SC, Lin JK, Wang HS, Yang SH, Fen-Yau Li A, Chang SC. Nuclear expression of CXCR4 is associated with advanced colorectal cancer. Int J Colorectal Dis. 2010;25:1185–91.

    Article  PubMed  Google Scholar 

  18. Yoshitake N, Fukui H, Yamagishi H, Sekikawa A, Fujii S, Ichikawa K, et al. Expression of SDF-1α and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer. 2008;98:1682–9.

    Article  CAS  PubMed  Google Scholar 

  19. Sobin LH. TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol. 2003;21:19–22.

    Article  PubMed  Google Scholar 

  20. Bustin SA. Absolute quantification of mRNA using real time reverse transcription polymerase chain reaction assays. J Mol Endocrinol. 2000;25:169–93.

    Article  CAS  PubMed  Google Scholar 

  21. Rubie C, Kempf K, Hans J, Su T, Tilton B, Georg T, et al. Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues. Mol Cell Probes. 2005;19:101–9.

    Article  CAS  PubMed  Google Scholar 

  22. Schoonjans F, Zalata A, Depuydt CE, Comhaire FH. MedCalc: a new computer program for medical statistics. Comput Methods Programs Biomed. 1995;48:257–62.

    Article  CAS  PubMed  Google Scholar 

  23. Kollmar O, Rupertus K, Scheuer C, Junker B, Tilton B, Schilling MK. Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis. Neoplasia. 2007;9:862–70.

    Article  CAS  PubMed  Google Scholar 

  24. Kollmar O, Rupertus K, Scheuer C, Nickels RM, Haberl GCY, Tilton B, et al. CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1. Int J Cancer. 2010;126:1302–15.

    CAS  PubMed  Google Scholar 

  25. Akishima-Fukasawa Y, Nakanishi Y, Ino Y, Morija Y, Kanai Y, Hirohashi S. Prognosticsignificance of CXCL12 expression in patients with colorectal carcinoma. Am J Clin Pathol. 2009;132:202–10.

    Article  CAS  PubMed  Google Scholar 

  26. Gassmann P, Haier J, Schlüter K, Domikowsky B, Wendel C, Wiesner U, et al. CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. Neoplasia. 2009;11:651–61.

    CAS  PubMed  Google Scholar 

  27. Brand S, Dambacher J, Beigel F, Olszak T, Diebold J, Otte JM, et al. CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Exp Cell Res. 2005;310:117–30.

    Article  CAS  PubMed  Google Scholar 

  28. Rubie C, Frick VO, Wagner M, Weber C, Kruse B, Kempf K, et al. Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases. World J Gastroenterol. 2006;12:6627–33.

    CAS  PubMed  Google Scholar 

  29. Ottaiano A, di Palma A, Napoletano M, Pisano C, Pignata S, Tatangelo F, et al. Inhibitory effects of anti-CXCR4 antibodies on human colon cancer cells. Cancer Immunol Immunother. 2005;54:781–91.

    Article  CAS  PubMed  Google Scholar 

  30. Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gönner U, Wilsberg V, et al. Effect of chemokine receptor CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res. 2005;11:1743–50.

    Article  CAS  PubMed  Google Scholar 

  31. Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C, et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann Surg. 2006;244:113–20.

    Article  PubMed  Google Scholar 

  32. Garber K. First results for agents targeting cancer-related inflammation. J Natl Cancer Inst. 2009;101:1110–2.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank C. Blinn, B. Kruse and C. Weber for excellent technical assistance.

Author information

Authors and Affiliations

  1. Department of General, Visceral, Vascular and Pediatric Surgery, University of the Saarland, Building 57, Homburg/Saar, 66421, Germany

    Vilma Oliveira Frick, Claudia Rubie, Sabrina K. Faust & Martin K. Schilling

  2. Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, 3010, Switzerland

    Pirus Ghadjar

  3. Institute of Pathology, University of the Saarland, Homburg/Saar, 66421, Germany

    Mathias Wagner

  4. Institute of Medical Biometrics, Epidemiology, and Medical Informatics (IMBEI), University of the Saarland, Homburg/Saar, 66421, Germany

    Stefan Gräber

Authors
  1. Vilma Oliveira Frick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Rubie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pirus Ghadjar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina K. Faust
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mathias Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefan Gräber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin K. Schilling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vilma Oliveira Frick.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oliveira Frick, V., Rubie, C., Ghadjar, P. et al. Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumor Biol. 32, 189–196 (2011). https://doi.org/10.1007/s13277-010-0112-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-010-0112-y

Keywords