Skip to main content

Advertisement

SpringerLink
Log in

IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

Gastric cancer is the world’s second most common malignancy and is a major threat to global health. IL-17, a CD4 T cell-derived mediator of angiogenesis, plays a major role in stimulating angiogenesis by regulating the production of a variety of proangiogenic factors, including the vascular endothelial growth factor (VEGF). The level of VEGF expression correlates with tumor progression and metastasis in gastric cancer tissues. Abnormal activation of signal transducer and activator of transcription 3 (Stat3) rendered the tumor cells highly angiogenic, which is manifested by an increased microvascular density (MVD) and considered it as a potential molecular marker for poor prognosis in gastric cancer angiogenesis. We determined that IL-17A-induced VEGF upregulation and neovascularization through a Stat3-mediated signaling pathway and hypothesized that blocking the Stat3 activation by using JSI-124, an inhibitor of phosphorylated Stat3, could significantly reduce the VEGF expression and can thus prevent angiogenesis. We showed an inhibition of angiogenesis and tumor progression when JSI-124 was treated with IL-17A in the cells and xenografts in an animal model and suggested that targeting the Stat pathway with JSI-124 could derive an effective therapeutic target for gastric cancers and could be a promising drug in gastric cancer treatment.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Smith MG, Hold GL, Tahara E, El-Omar EM. Cellular and molecular aspects of gastric cancer. World J Gastroenterol. 2006;12:2979–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Meng XY, Zhou CH, Ma J, Jiang C, Ji P. Expression of interleukin-17 and its clinical significance in gastric cancer patients. Med Oncol. 2012;29:3024–8.

    Article  CAS  PubMed  Google Scholar 

  3. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–43.

    Article  CAS  PubMed  Google Scholar 

  4. Correa P. Helicobacter pylori and gastric cancer: state of the art. Cancer Epidemiol Biomarkers Prev. 1996;5:477–81.

    CAS  PubMed  Google Scholar 

  5. Chen WQ. Estimation of cancer incidence and mortality in China in 2004–2005. Zhonghua Zhong Liu Za Zhi. 2009;31:664–8.

    PubMed  Google Scholar 

  6. Bornschein J, Kandulski A, Selgrad M, Malfertheiner P. From gastric inflammation to gastric cancer. Dig Dis. 2010;28:609–14.

    Article  PubMed  Google Scholar 

  7. Chen JG, Xia JC, Liang XT, Pan K, Wang W, Lv L, et al. Intratumoral expression of IL-17 and its prognostic role in gastric adenocarcinoma patients. Int J Biol Sci. 2011;7:53–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008;8:337–48.

    Article  CAS  PubMed  Google Scholar 

  9. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, et al. Cutting edge: TH17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol. 2007;178:6730–3.

    Article  CAS  PubMed  Google Scholar 

  10. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al. Phenotype, distribution, generation, and functional and clinical relevance of TH17 cells in the human tumor environments. Blood. 2009;114:1141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008;14:3254–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7.

    Article  CAS  PubMed  Google Scholar 

  13. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating vegf production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011;407:348–54.

    Article  CAS  PubMed  Google Scholar 

  14. Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, et al. Tumor-infiltrating CD4+ TH17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 2011;25:1271–7.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, et al. The prevalence of TH17 cells in patients with gastric cancer. Biochem Biophys Res Commun. 2008;374:533–7.

    Article  CAS  PubMed  Google Scholar 

  16. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931–4.

    CAS  PubMed  Google Scholar 

  17. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.

    Article  CAS  PubMed  Google Scholar 

  18. Zhao M, WB C, JX Z, YW Y Effect of vascular endothelial growth factor on adhesion of large intestine cancer cell ht-29, 2000, 8, pp 646-649.

  19. Yan J, Chen W, Ma Y, Sun X. Expression of vascular endothelial growth factor in liver tissues of hepatitis B. Zhonghua Gan Zang Bing Za Zhi. 2000;8:150–2.

    CAS  PubMed  Google Scholar 

  20. Xue JT, Wu J, Meng L, Dong ZW, Shou CC. Expression of VEGF(121) in gastric carcinoma MGC803 cell line. World J Gastroenterol. 2000;6:281–3.

    PubMed  Google Scholar 

  21. Zhang H, Wu J, Meng L, Shou CC. Expression of vascular endothelial growth factor and its receptors KDR and FLT-1 in gastric cancer cells. World J Gastroenterol. 2002;8:994–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.

    Article  CAS  PubMed  Google Scholar 

  23. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84:1875–87.

    Article  CAS  PubMed  Google Scholar 

  24. Weidner N. Tumor angiogenesis: review of current applications in tumor prognostication. Semin Diagn Pathol. 1993;10:302–13.

    CAS  PubMed  Google Scholar 

  25. Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res. 2005;11:1386–93.

    Article  CAS  PubMed  Google Scholar 

  26. Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 2002;21:7001–10.

    Article  CAS  PubMed  Google Scholar 

  27. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003;22:319–29.

    Article  CAS  PubMed  Google Scholar 

  28. Tan M, Li Z, Ma S, Luo J, Xu S, Lu A, et al. Heroin activates Bim via c-Jun N-terminal kinase/c-Jun pathway to mediate neuronal apoptosis. Neuroscience. 2013;233:1–8.

    Article  CAS  PubMed  Google Scholar 

  29. Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, et al. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Investig. 1992;67:519–28.

    CAS  PubMed  Google Scholar 

  30. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52.

    Article  CAS  PubMed  Google Scholar 

  32. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467–76.

    Article  CAS  PubMed  Google Scholar 

  33. Tenderenda M, Rutkowski P, Jesionek-Kupnicka D, Kubiak R. Expression of CD34 in gastric cancer and its correlation with histology, stage, proliferation activity, p53 expression and apoptotic index. Pathol Oncol Res. 2001;7:129–34.

    Article  CAS  PubMed  Google Scholar 

  34. Guset G, Costi S, Lazar E, Dema A, Cornianu M, Vernic C, et al. Expression of vascular endothelial growth factor (VEGF) and assessment of microvascular density with CD34 as prognostic markers for endometrial carcinoma. Rom J Morphol Embryol. 2010;51:677–82.

    CAS  PubMed  Google Scholar 

  35. Schlingemann RO, Rietveld FJ, de Waal RM, Bradley NJ, Skene AI, Davies AJ, et al. Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma. Lab Investig. 1990;62:690–6.

    CAS  PubMed  Google Scholar 

  36. Xie K, Wei D, Shi Q, Huang S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev. 2004;15:297–324.

    Article  CAS  PubMed  Google Scholar 

  37. Alexandrakis MG, Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A, et al. Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma. Eur J Int Med. 2006;17:412–6.

    Article  CAS  Google Scholar 

  38. Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995;269:81–3.

    Article  CAS  PubMed  Google Scholar 

  39. Roskoski RJ. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 2007;62:179–213.

    Article  PubMed  Google Scholar 

  40. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, et al. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. Apmis. 2006;114:619–25.

    Article  CAS  PubMed  Google Scholar 

  41. Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, et al. Stat3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene. 2004;23:4921–9.

    Article  CAS  PubMed  Google Scholar 

  42. Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002;62:6659–66.

    CAS  PubMed  Google Scholar 

  43. Burke WM, Jin X, Lin HJ, Huang M, Liu R, Reynolds RK, et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 2001;20:7925–34.

    Article  CAS  PubMed  Google Scholar 

  44. Lee DH, Iwanski GB, Thoennissen NH. Cucurbitacin: ancient compound shedding new light on cancer treatment. Sci World J. 2010;10:413–8.

    Article  CAS  Google Scholar 

  45. Molavi O, Ma Z, Hamdy S, Lai R, Lavasanifar A, Samuel J. Synergistic antitumor effects of CpG oligodeoxynucleotide and Stat3 inhibitory agent JSI-124 in a mouse melanoma tumor model. Immunol Cell Biol. 2008;86:506–14.

    Article  CAS  PubMed  Google Scholar 

  46. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs. 2005;16:601–7.

    Article  CAS  PubMed  Google Scholar 

  47. Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of Stat3 by curcurbitacin-i (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther. 2010;9:3302–14.

    Article  CAS  PubMed  Google Scholar 

  48. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin i), a selective janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res. 2003;63:1270–9.

    CAS  PubMed  Google Scholar 

  49. Wang L, Yi T, Zhang W, Pardoll DM, Yu H. IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res. 2010;70:10112–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol. 2009;50:980–9.

    Article  CAS  PubMed  Google Scholar 

  51. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity upregulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21:2000–8.

    Article  CAS  PubMed  Google Scholar 

  52. Chen Z, Han ZC. Stat3: a critical transcription activator in angiogenesis. Med Res Rev. 2008;28:185–200.

    Article  CAS  PubMed  Google Scholar 

  53. Kim NH, Lee MY, Park SJ, Choi JS, Oh MK, Kim IS. Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and Stat3. Immunology. 2007;122:607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, et al. Capsaicin is a novel blocker of constitutive and interleukin-6-inducible Stat3 activation. Clin Cancer Res. 2007;13:3024–32.

    Article  CAS  PubMed  Google Scholar 

  55. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.81201931) and the Guangdong Natural Science Funds for Distinguished Young Scholar (No. S2013050014121) and a Research Award Fund for Outstanding Young Teachers in Guangdong Provincial Higher Education Institutions (Grant No. Yq2013133).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510182, China

    Xiaoqin Wu, Tao Yang, Xiang Liu, Jia nian Guo, Tingting Xie, Yuanwei Ding, Manpeng Lin & Hui Yang

Authors
  1. Xiaoqin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia nian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuanwei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manpeng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaoqin Wu or Hui Yang.

Ethics declarations

Human/animal studies have been approved by The Institute of Medical Research Ethics Committee of Guangzhou Medical University. All participants enrolled in the study signed the informed consent forms. All human studies were followed in accordance with the ethical standards laid down in 1964 Declaration of Helsinki and its amendments.

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Yang, T., Liu, X. et al. IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer. Tumor Biol. 37, 5493–5501 (2016). https://doi.org/10.1007/s13277-015-4372-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4372-4

Keywords

Search

Navigation