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Tumor Biology

, Volume 37, Issue 2, pp 2415–2423 | Cite as

The chemokine receptor CXCR7 is a critical regulator for the tumorigenesis and development of papillary thyroid carcinoma by inducing angiogenesis in vitro and in vivo

  • Hengwei Zhang
  • Lei Yang
  • Xuyong Teng
  • Zhangyi Liu
  • Chenxi Liu
  • Lei Zhang
  • Zhen Liu
Original Article

Abstract

Papillary thyroid carcinoma (PTC) is a well-differentiated neoplasm, but it can transfer early to cervical lymph nodes. Accumulating evidences have confirmed the important roles of CXCR7 in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study demonstrated CXCR7 modulated proliferation, apoptosis, and invasion of PTC cells. In this study, we evaluated the effect of expression of CXCR7 in PTC cells on angiogenesis and whether its expression had an influence on the tumor growth of PTC in vivo. We evaluated the effect of CXCR7 on interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) secretion, angiogenesis, and tumor growth by ELISA, endothelial tube formation assay, and a xenograft tumor model in nude mice. Immunohistochemistry was used to assess expression of CD34 in tumor of mice. In vitro and in vivo studies in PTC cells suggested that the alteration of CXCR7 expression was correlated with angiogenesis and tumor growth. Moreover, CXCR7 mediated the expression of IL-8 and VEGF, which might be involved in the regulation of tumor angiogenesis. These findings suggest that CXCR7 affects the growth of PTC cells and participates in the tumorigenesis of PTC, probably through regulating angiogenesis by the proangiogenic VEGF or IL-8.

Keywords

Thyroid neoplasms Chemokine receptor CXCR7 Interleukin-8 Vascular endothelial growth factor Angiogenesis 

Notes

Acknowledgments

This project was supported by the National Nature Science Foundation of China (81072182) and Liaoning Provincial Nature Science Foundation (2013021100).

Authors’ contributions

Liu Z designed the study and revised the manuscript. Zhang HW and Yang L performed the experiments except ELISA and immunohistochemistry assay, and drafted the manuscript. Teng XY and Liu ZY performed the ELISA and immunohistochemistry assay. Liu CX and Zhang L participated in the experiments and performed data statistics. All authors read and approved the final manuscript.

Compliance with ethical standards

Ethical approval

All procedures performed in this study involving animals were in accordance with the ethical standards of the institution in the Affiliated Shengjing Hospital of China Medical University.

Conflicts of interest

None

References

  1. 1.
    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;36:401–10.CrossRefGoogle Scholar
  2. 2.
    Ben-Baruch A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin Exp Metastasis. 2008;25:345–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005;280:35760–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–13.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boldajipour B, Mahabaleshwar H, Kardash E, et al. Control of chemokine-guided cell migration by ligand sequestration. Cell. 2008;132:463–73.CrossRefPubMedGoogle Scholar
  7. 7.
    Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A. 2007;104:15735–40.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Heinrich EL, Lee W, Lu J, et al. Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells. J Transl Med. 2012;10:68.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Xue TC, Han D, Chen RX, et al. High expression of CXCR7 combined with alpha fetoprotein in hepatocellular carcinoma correlates with extra-hepatic metastasis to lung after hepatectomy. Asian Pac J Cancer Prev. 2011;12:657–63.PubMedGoogle Scholar
  10. 10.
    Yu Y, Li H, Xue B, et al. SDF-1/CXCR7 axis enhances ovarian cancer cell invasion by MMP-9 expression through p38 MAPK pathway. DNA Cell Biol. 2014;33:543–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Li XX, Zheng HT, Huang LY, et al. Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and β-arrestin pathways. Int J Oncol. 2014;45:1649–57.PubMedGoogle Scholar
  12. 12.
    Zheng K, Li HY, Su XL, et al. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2010;29:31.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Singh RK, Lokeshwar BL. The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res. 2011;71:3268–77.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol. 2012;84:204–14.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu Z, Sun DX, Teng XY, et al. Expression of stromal cell-derived factor 1 and CXCR7 in papillary thyroid carcinoma. Endocr Pathol. 2012;23:247–53.CrossRefPubMedGoogle Scholar
  16. 16.
    Liu Z, Yang L, Teng X, et al. The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma. J Surg Res. 2014;191:379–88.CrossRefPubMedGoogle Scholar
  17. 17.
    Liberman J, Sartelet H, Flahaut M, et al. Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma. PLoS One. 2012;7:e43665.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol. 2012;10:212.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tachezy M, Zander H, Gebauer F, et al. CXCR7 expression in esophageal cancer. J Transl Med. 2013;11:238.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wani N, Nasser MW, Ahirwar DK, et al. C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Res. 2014;16:R54.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Xue TC, Chen RX, Han D, et al. Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med. 2012;3:117–23.PubMedGoogle Scholar
  22. 22.
    Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 2008;283:4283–94.CrossRefPubMedGoogle Scholar
  23. 23.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Hernandez L, Magalhaes MA, Coniglio SJ, et al. Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis. Breast Cancer Res. 2011;13:R128.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Totonchy JE, Clepper L, Phillips KG, et al. CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion. Cell Adhes Migr. 2014;8:165–76.CrossRefGoogle Scholar
  26. 26.
    Maishi N, Ohga N, Hida Y, et al. CXCR7: a novel tumor endothelial marker in renal cell carcinoma. Pathol Int. 2012;62:309–17.CrossRefPubMedGoogle Scholar
  27. 27.
    Kollmar O, Rupertus K, Scheuer C, et al. CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1. Int J Cancer. 2010;126:1302–15.PubMedGoogle Scholar
  28. 28.
    Bauerle KT, Schweppe RE, Lund G, et al. Nuclear factor κB-dependent regulation of angiogenesis, and metastasis in an in vivo model of thyroid cancer is associated with secreted interleukin-8. J Clin Endocrinol Metab. 2014;99:E1436–44.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nagasaki T, Hara M, Nakanishi H, et al. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 2014;110:469–78.CrossRefPubMedGoogle Scholar
  30. 30.
    Xie TX, Xia Z, Zhang N, et al. Constitutive NF-kappaB activity regulates the expression of VEGF and IL-8 and tumor angiogenesis of human glioblastoma. Oncol Rep. 2010;23:725–32.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang E, Feng X, Liu F, et al. Roles of PI3K/Akt and c-Jun signaling pathways in human papillomavirus type 16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis in non-small cell lung cancer cells. PLoS One. 2014;9:e103440.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Hengwei Zhang
    • 1
  • Lei Yang
    • 2
  • Xuyong Teng
    • 1
  • Zhangyi Liu
    • 1
  • Chenxi Liu
    • 1
  • Lei Zhang
    • 1
  • Zhen Liu
    • 1
  1. 1.Department of General Surgery, Shengjing HospitalChina Medical UniversityShenyangChina
  2. 2.Department of General Surgery, First Affiliated HospitalChina Medical UniversityShenyangChina

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