Skip to main content
SpringerLink
Log in

Chemokine and chemokine receptor patterns in patients with benign and malignant salivary gland tumors: a distinct role for CCR7

  • Research Article
  • Published:
European Cytokine Network Aims and scope

Abstract

Background

To explore the molecular mechanisms involved in pathophysiology of malignant and benign salivary gland tumors (SGTs), we investigated main tumor-inducing chemokines and chemokine receptors, CXCL12/CXCR4/ACKR3 (CXCR7), CXCR3/CXCL10, CCR5/CCL5, CCL21/CCR7, CCL2, CCR4, CXCR5, CCR6, and CXCL8 in tumor tissues.

Patients and methods

Parotid tissues were obtained from 30 patients with malignant and benign SGTs. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the mRNA expression pattern of the mentioned chemokines/chemokine receptors and immunohistochemistry (IHC) was performed to verify the expression of CCR7.

Results

Expression levels of CCR7 and CCR4 transcripts were higher in the tumor tissues of malignant cases in comparison to benign ones (p = 0.03 and 0.02). Immunohistochemistry analysis confirmed that the protein level of CCR7 concurred with the mRNA expression. CCL2 gene transcripts were observed with a higher expression in patients with tumor-free lymph nodes (LN–) and early stages, whereas CCR7 transcript was higher in LN+ and late stages of the disease. A significant inverse correlation was found between CXCL10 transcript and tumor size in benign cases. The mRNA expression of CCR7, CCR4, CXCR3, CCL21, CCL5, and CXCL12 was significantly higher in mucoepidermoid carcinoma in comparison to pleomorphic adenoma subtypes (p < 0.05).

Conclusion

On the basis of the present study, it was determined that malignant and benign SGTs exhibit a distinct pattern of chemokines and chemokine receptors, which are probably associated with known biological and clinical behaviors of these tumors. Significant increased CCR4 and CCR7 expression in malignant SGTs might play a central role in malignant transformation that introduces them as new targets for cancer immunotherapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Speight PM, Barrett AW. Salivary gland tumours. Oral Dis 2002; 8: 229–40.

    Article  CAS  PubMed  Google Scholar 

  2. Jaso J, Malhotra R. Adenoid cystic carcinoma. Arch Pathol Lab Med 2011; 135: 511–5.

    PubMed  Google Scholar 

  3. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–22.

    Article  CAS  PubMed  Google Scholar 

  4. da Silva JM, Soave DF, Moreira Dos Santos TP, et al. Significance of chemokine and chemokine receptors in head and neck squamous cell carcinoma: a critical review. Oral Oncol 2016; 56: 8–16.

    Article  PubMed  Google Scholar 

  5. Haghshenas MR, Khademi B, Ashraf MJ, Ghaderi A, Erfani N. Helper and cytotoxic T-cell subsets (Th1, Th2, Tc1, and Tc2) in benign and malignant salivary gland tumors. Oral Dis 2016; 22: 566–72.

    Article  CAS  PubMed  Google Scholar 

  6. Haghshenas MR, Khademi B, Faghih Z, Ghaderi A, Erfani N. Immune regulatory cells and IL17-producing lymphocytes in patients with benign and malignant salivary gland tumors. Immunol Lett 2015; 164: 109–16.

    Article  CAS  PubMed  Google Scholar 

  7. Bachelerie F, Ben-Baruch A, Burkhardt AM, et al. International Union of Basic and Clinical Pharmacology. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 2014; 66: 1–79.

    PubMed  Google Scholar 

  8. Balkwill FR. The chemokine system and cancer. J Pathol 2012; 226: 148–57.

    Article  CAS  PubMed  Google Scholar 

  9. Chow MT, Luster AD. Chemokines in cancer. Cancer Immunol Res 2014; 2: 1125–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lou H, Fang J, Li P, et al. Frequency, suppressive capacity, recruitment and induction mechanisms of regulatory T cells in sinonasal squamous cell carcinoma and nasal inverted papilloma. PLoS One 2015; 10: e0126463.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942–9.

    Article  CAS  PubMed  Google Scholar 

  12. Razmkhah M, Jaberipour M, Safaei A, Talei AR, Erfani N, Ghaderi A. Chemokine and chemokine receptors: a comparative study between metastatic and nonmetastatic lymph nodes in breast cancer patients. Eur Cytokine Netw 2012; 23: 72–7.

    CAS  PubMed  Google Scholar 

  13. Liu FY, Safdar J, Li ZN, et al. CCR7 regulates cell migration and invasion through MAPKs in metastatic squamous cell carcinoma of head and neck. Int J Oncol 2014; 45: 2502–10.

    CAS  PubMed  Google Scholar 

  14. Ueda M, Shimada T, Goto Y, et al. Expression of CC-chemokine receptor 7 (CCR7) and CXC-chemokine receptor 4 (CXCR4) in head and neck squamous cell carcinoma. Auris Nasus Larynx 2010; 37: 488–95.

    Article  PubMed  Google Scholar 

  15. Liu XY, Song L, Wang Z. CCR7: A metastasis and prognosis indicator of postoperative patients with esophageal carcinoma. Hepatogastroenterology 2013; 60: 747–50.

    CAS  PubMed  Google Scholar 

  16. Du P, Liu Y, Ren H, et al. Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis. Gastric Cancer 2017; 20: 235–45.

    Article  CAS  PubMed  Google Scholar 

  17. Shi M, Chen D, Yang D, Liu XY. CCL21-CCR7 promotes the lymph node metastasis of esophageal squamous cell carcinoma by up-regulating MUC1. J Exp Clin Cancer Res 2015; 34:149.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chen J, Cui YU, Liu L, et al. CCR7 as a predictive biomarker associated with computed tomography for the diagnosis of lymph node metastasis in bladder carcinoma. Oncol Lett 2016; 11: 735–40.

    PubMed  Google Scholar 

  19. Sperveslage J, Frank S, Heneweer C, et al. 215: The role of chemokine receptor CCR7 and Its ligands CCL19 and CCL21 in tumor progression of pancreatic ductal adenocarcinoma. Cytokine 2013; 63:302.

    Article  Google Scholar 

  20. Tsujikawa T, Yaguchi T, Ohmura G, et al. Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma. Int J Cancer 2013; 132: 2755–66.

    Article  CAS  PubMed  Google Scholar 

  21. Yang Y, Du L, Yang X, et al. AberrantCCR4expression is involved in tumor invasion of lymph node-negative human gastric cancer. PLoS One 2015; 10: e0120059.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mardani M, Andisheh Tadbir A, Khademi B, Melekzadeh M, Vaziri L. Decreased serum monocyte chemoattractant protein1 in salivary gland tumor patients. Asian Pac J Cancer Prev 2016; 17: 3601–4.

    PubMed  Google Scholar 

  23. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29: 313–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Suzuki S, Maeda A, Miura M, Ozeki S. Involvement of chemokine receptor 4/stromal cell-derived factor 1 system in human salivary gland carcinoma motility. Oral Sci Int 2006; 3: 13–20.

    Article  Google Scholar 

  25. Uchida D, Kuribayashi N, Kinouchi M, et al. Expression and function of CXCR4 in human salivary gland cancers. Clin Exp Metastasis 2013; 30: 133–42.

    Article  CAS  PubMed  Google Scholar 

  26. Shen Z, Li T, Chen D, et al. The CCL5/CCR5 axis contributes to the perineural invasion of human salivary adenoid cystic carcinoma. Oncol Rep 2014; 31: 800–6.

    CAS  PubMed  Google Scholar 

  27. Lanzel E, Robinson RA, Zimmerman MB, Pourian A, Hellstein JW. The use of immunohistochemistry in detection of perineural invasion in mucoepidermoid carcinoma. Oral Surg Oral Med OralPathol Oral Radiol 2016; 121: 636–42.

    Article  Google Scholar 

  28. Barrett AW, Speight PM. Perineural invasion in adenoid cystic carcinoma of the salivary glands: a valid prognostic indicator? Oral Oncol 2009; 45: 936–40.

    Article  PubMed  Google Scholar 

  29. Ma B, Khazali A, Wells A. CXCR3 in carcinoma progression. Histol Histopathol 2015; 30: 781–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kondo T, Ito F, Nakazawa H, Horita S, Osaka Y, Toma H. High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma. J Urol 2004; 171: 2171–5.

    Article  CAS  PubMed  Google Scholar 

  31. Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (Review). Oncol Lett 2011; 2: 583–9.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Reza Haghshenas, Abbas Ghaderi, Nasrollah Erfani & Mahboobeh Razmkhah

  2. Department of Pathology, Khalili Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Javad Ashraf

  3. Otolaryngology Research Center, Department of Otolaryngology, Shiraz University of Medical Sciences, Shiraz, Iran

    Bijan Khademi

  4. Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Abbas Ghaderi

Authors
  1. Mohammad Reza Haghshenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Javad Ashraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bijan Khademi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abbas Ghaderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nasrollah Erfani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mahboobeh Razmkhah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Abbas Ghaderi or Mahboobeh Razmkhah.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haghshenas, M.R., Ashraf, M.J., Khademi, B. et al. Chemokine and chemokine receptor patterns in patients with benign and malignant salivary gland tumors: a distinct role for CCR7. Eur Cytokine Netw 28, 27–35 (2017). https://doi.org/10.1684/ecn.2017.0388

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1684/ecn.2017.0388

Key words

Search

Navigation