Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma

Oncogene volume 37, pages 873–883 (2018)Cite this article

Subjects

A Correction to this article was published on 18 September 2023

This article has been updated

Abstract

Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial–mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6–CXCR7 axis may provide a promising target for the treatment of ESCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Change history

References

  1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG . Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13: 714–726.

    Article  CAS  Google Scholar 

  2. McMillin DW, Negri JM, Mitsiades CS . The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 2013; 12: 217–228.

    Article  CAS  Google Scholar 

  3. Morin PJ . Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat 2003; 6: 169–172.

    Article  CAS  Google Scholar 

  4. Shi WJ, Gao JB . Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8: 673–681.

    Article  Google Scholar 

  5. Velaei K, Samadi N, Barazvan B, Soleimani Rad J . Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 2016; 30: 92–100.

    Article  Google Scholar 

  6. Villanueva MT . Cell signalling: Stuck in the middle of chemoresistance and metastasis. Nat Rev Clin Oncol 2012; 9: 490.

    Article  Google Scholar 

  7. Wilson BJ, Saab KR, Ma J, Schatton T, Putz P, Zhan Q et al. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res 2014; 74: 4196–4207.

    Article  CAS  Google Scholar 

  8. Park YH, Sohn SK, Kim JG, Lee MH, Song HS, Kim MK et al. Interaction between BCL2 and interleukin-10 gene polymorphisms alter outcomes of diffuse large B-cell lymphoma following rituximab plus CHOP chemotherapy. Clin Cancer Res 2009; 15: 2107–2115.

    Article  CAS  Google Scholar 

  9. Heinecke JL, Ridnour LA, Cheng RY, Switzer CH, Lizardo MM, Khanna C et al. Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proc Natl Acad Sci USA 2014; 111: 6323–6328.

    Article  CAS  Google Scholar 

  10. Bid HK, Kibler A, Phelps DA, Manap S, Xiao L, Lin J et al. Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma. Clin Cancer Res 2013; 19: 6716–6729.

    Article  CAS  Google Scholar 

  11. Korkaya H, Liu S, Wicha MS . Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res 2011; 17: 6125–6129.

    Article  CAS  Google Scholar 

  12. Alas S, Emmanouilides C, Bonavida B . Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res 2001; 7: 709–723.

    CAS  PubMed  Google Scholar 

  13. Vandercappellen J, Van Damme J, Struyf S . The role of CXC chemokines and their receptors in cancer. Cancer Lett 2008; 267: 226–244.

    Article  CAS  Google Scholar 

  14. Balkwill FR . The chemokine system and cancer. J Pathol 2012; 226: 148–157.

    Article  CAS  Google Scholar 

  15. Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M . CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 2005; 24: 4462–4471.

    Article  CAS  Google Scholar 

  16. Calinescu AA, Yadav VN, Carballo E, Kadiyala P, Tran D, Zamler DB et al. Survival and proliferation of neural progenitor-derived glioblastomas under hypoxic stress is controlled by a CXCL12/CXCR4 autocrine-positive feedback mechanism. Clin Cancer Res 2017; 23: 1250–1262.

    Article  CAS  Google Scholar 

  17. Gil M, Seshadri M, Komorowski MP, Abrams SI, Kozbor D . Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases. Proc Natl Acad Sci USA 2013; 110: E1291–E1300.

    Article  CAS  Google Scholar 

  18. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    Article  CAS  Google Scholar 

  19. Pennathur A, Gibson MK, Jobe BA, Luketich JD . Oesophageal carcinoma. Lancet 2013; 381: 400–412.

    Article  Google Scholar 

  20. Enzinger PC, Mayer RJ . Esophageal cancer. N Engl J Med 2003; 349: 2241–2252.

    Article  CAS  Google Scholar 

  21. Schweigert M, Dubecz A, Stein HJ . Oesophageal cancer—an overview. Nat Rev Gastroenterol Hepatol 2013; 10: 230–244.

    Article  CAS  Google Scholar 

  22. Demeester SR . Reoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut 2005; 54: 440–441.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang LH, Yang XY, Zhang X, Huang J, Hou J, Li J et al. Transcriptional inactivation of STAT3 by PPARgamma suppresses IL-6-responsive multiple myeloma cells. Immunity 2004; 20: 205–218.

    Article  CAS  Google Scholar 

  24. Smith MR, Xie T, Joshi I, Schilder RJ . Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells. Br J Haematol 1998; 102: 1090–1097.

    Article  CAS  Google Scholar 

  25. Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, Schall TJ et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 2010; 70: 3299–3308.

    Article  CAS  Google Scholar 

  26. Lippitz BE, Harris RA . Cytokine patterns in cancer patients: a review of the correlation between interleukin 6 and prognosis. Oncoimmunology 2016; 5: e1093722.

    Article  Google Scholar 

  27. Baggiolini M . Chemokines and leukocyte traffic. Nature 1998; 392: 565–568.

    Article  CAS  Google Scholar 

  28. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK . CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 2011; 17: 2074–2080.

    Article  CAS  Google Scholar 

  29. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 2010; 107: 20009–20014.

    Article  CAS  Google Scholar 

  30. Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 2010; 29: 709–722.

    Article  CAS  Google Scholar 

  31. Teicher BA, Fricker SP . CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010; 16: 2927–2931.

    Article  CAS  Google Scholar 

  32. Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA 2007; 104: 14759–14764.

    Article  CAS  Google Scholar 

  33. Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA 2007; 104: 15735–15740.

    Article  CAS  Google Scholar 

  34. Zhao S, Chang SL, Linderman JJ, Feng FY, Luker GD . A comprehensive analysis of CXCL12 isoforms in breast cancer1,2. Transl Oncol 2014; 7: 429–438.

    Article  Google Scholar 

  35. Tachezy M, Zander H, Gebauer F, von Loga K, Pantel K, Izbicki JR et al. CXCR7 expression in esophageal cancer. J Transl Med 2013; 11: 238.

    Article  Google Scholar 

  36. Wu K, Cui L, Yang Y, Zhao J, Zhu D, Liu D et al. Silencing of CXCR2 and CXCR7 protects against esophageal cancer. Am J Transl Res 2016; 8: 3398–3408.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J 2004; 18: 1240–1242.

    Article  CAS  Google Scholar 

  38. Hinton CV, Avraham S, Avraham HK . Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 2010; 27: 97–105.

    Article  CAS  Google Scholar 

  39. Liu J, Liao S, Huang Y, Samuel R, Shi T, Naxerova K et al. PDGF-D improves drug delivery and efficacy via vascular normalization, but promotes lymphatic metastasis by activating CXCR4 in breast cancer. Clin Cancer Res 2011; 17: 3638–3648.

    Article  CAS  Google Scholar 

  40. Goto M, Yoshida T, Yamamoto Y, Furukita Y, Inoue S, Fujiwara S et al. CXCR4 expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Ann Surg Oncol 2017; 24: 832–840.

    Article  Google Scholar 

  41. Zhang L, Ye SB, Ma G, Tang XF, Chen SP, He J et al. The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma. J Transl Med 2013; 11: 60.

    Article  Google Scholar 

  42. Lin L, Han MM, Wang F, Xu LL, Yu HX, Yang PY . CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression. Cell Death Dis 2014; 5: e1488.

    Article  CAS  Google Scholar 

  43. Jin Z, Nagakubo D, Shirakawa AK, Nakayama T, Shigeta A, Hieshima K et al. CXCR7 is inducible by HTLV-1 Tax and promotes growth and survival of HTLV-1-infected T cells. Int J Cancer 2009; 125: 2229–2235.

    Article  CAS  Google Scholar 

  44. Kerdivel G, Boudot A, Pakdel F . Estrogen represses CXCR7 gene expression by inhibiting the recruitment of NFkappaB transcription factor at the CXCR7 promoter in breast cancer cells. Biochem Biophys Res Commun 2013; 431: 729–733.

    Article  CAS  Google Scholar 

  45. Liu FY, Zhao ZJ, Li P, Ding X, Guo N, Yang LL et al. NF-kappaB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck. Oncol Rep 2011; 25: 383–391.

    CAS  PubMed  Google Scholar 

  46. Tarnowski M, Grymula K, Reca R, Jankowski K, Maksym R, Tarnowska J et al. Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas. Mol Cancer Res 2010; 8: 1–14.

    Article  CAS  Google Scholar 

  47. Tarnowski M, Liu R, Wysoczynski M, Ratajczak J, Kucia M, Ratajczak MZ . CXCR7: a new SDF-1-binding receptor in contrast to normal CD34(+) progenitors is functional and is expressed at higher level in human malignant hematopoietic cells. Eur J Haematol 2010; 85: 472–483.

    Article  CAS  Google Scholar 

  48. Wu YC, Tang SJ, Sun GH, Sun KH . CXCR7 mediates TGFbeta1-promoted EMT and tumor-initiating features in lung cancer. Oncogene 2016; 35: 2123–2132.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81171986), Research Grant from the Ministry of Public Health (Grant No. 201501004) and the Basic and Advanced Technology Research Foundation from Science and Technology Department of Henan Province (Grant Nos. 112300410153 and 122300410155).

Author information

Author notes

  1. Y Qiao and C Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Y Qiao, C Zhang, A Li, D Wang, Z Luo, Y Ping, B Zhou, S Liu, H Li, D Yue, Z Zhang, X Chen, Z Shen, J Lian, Y Li, S Wang, F Li, L Huang & Y Zhang

  2. Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Y Qiao, C Zhang, A Li, D Wang, Z Luo, D Yue, X Chen, Z Shen, S Wang, L Wang & Y Zhang

  3. School of Life Sciences, Zhengzhou University, Zhengzhou, China

    B Zhou, S Liu, J Lian, Y Li & Y Zhang

  4. Department of Hematology/Oncology, School of Medicine, Northwestern University, Chicago, IL, USA

    B Zhang

  5. Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    J Yu

  6. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Z Qin

  7. Key Laboratory for Tumor Immunology and Biotherapy of Henan Province, Zhengzhou, China

    Y Zhang

Authors
  1. Y Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Ping
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Z Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. X Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Z Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. F Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. L Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. B Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. J Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Z Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiao, Y., Zhang, C., Li, A. et al. IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene 37, 873–883 (2018). https://doi.org/10.1038/onc.2017.387

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.387

This article is cited by

Search

Advanced search

Quick links