Skip to main content

Advertisement

SpringerLink
Log in

TIPE1 suppresses osteosarcoma tumor growth by regulating macrophage infiltration

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Osteosarcoma is the most common primary malignancy of the bone, and macrophages play a promotional role during osteosarcoma development and progression. TIPE1 is known to function as a tumor suppressor in diverse cancers by inducing cell arrest and apoptosis. However, the biological function of TIPE1 in osteosarcoma is still unclear.

Purpose

The purpose of this study was to investigate the expression and function of TIPE1 in osteosarcoma.

Methods

In the present study, TIPE1 expression in osteosarcoma cancer cells was determined by qPCR and western blotting. A subcutaneous tumor model was established to investigate the potential anti-tumor activity of TIPE1 in osteosarcoma. Further, flow cytometry, western blotting, immunofluorescence staining, and ELISA were performed to clarify the underlying mechanism by which TIPE1 regulates growth of osteosarcoma.

Results

Our results suggest that TIPE1 is downregulated in osteosarcoma cancer cells, and ectopic expression TIPE1 significantly inhibited osteosarcoma tumor growth in vivo. Furthermore, TIPE1 inhibits the infiltration of macrophages in osteosarcoma tumor by suppressing MCP-1 expression in osteosarcoma cells. Further in vivo study revealed that inhibition of MCP-1/CCR2 axis by Bindarit blocked the inhibitory effect of TIPE1 on osteosarcoma growth.

Conclusion

Collectively, our results demonstrate the anti-tumor role of TIPE1 in osteosarcoma and reveal a novel therapy target for osteosarcoma.

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

Data availability

Data and materials supporting the findings of this study are available within the article.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. https://doi.org/10.3322/caac.21332.

    Article  PubMed  Google Scholar 

  3. Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer. 2003;98(11):2447–56. https://doi.org/10.1002/cncr.11799.

    Article  PubMed  Google Scholar 

  4. Bielack SS, Kempf-Bielack B, Branscheid D, Carrle D, Friedel G, Helmke K, et al. Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol. 2009;27(4):557–65. https://doi.org/10.1200/jco.2008.16.2305.

    Article  PubMed  Google Scholar 

  5. Rivera-Valentin RK, Zhu L, Hughes DP. Bone sarcomas in pediatrics: progress in our understanding of tumor biology and implications for therapy. Paediatr Drugs. 2015;17(4):257–71. https://doi.org/10.1007/s40272-015-0134-4.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Biermann JS, Chow W, Reed DR, Lucas D, Adkins DR, Agulnik M, et al. NCCN Guidelines Insights: bone Cancer, Version 2.2017. J Natl Compr Cancer Netw: JNCCN. 2017;15(2):155–67.

    Article  Google Scholar 

  7. Marx J. Cancer biology. All in the stroma: cancer’s Cosa Nostra. Science (New York, NY). 2008;320(5872):38–41. https://doi.org/10.1126/science.320.5872.38.

    Article  CAS  Google Scholar 

  8. Yuan Y, Jiang YC, Sun CK, Chen QM. Role of the tumor microenvironment in tumor progression and the clinical applications (review). Oncol Rep. 2016;35(5):2499–515. https://doi.org/10.3892/or.2016.4660.

    Article  CAS  PubMed  Google Scholar 

  9. Casey SC, Amedei A, Aquilano K, Azmi AS, Benencia F, Bhakta D, et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol. 2015;35:S199–223. https://doi.org/10.1016/j.semcancer.2015.02.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rhee I. Diverse macrophages polarization in tumor microenvironment. Arch Pharmacal Res. 2016;39(11):1588–96. https://doi.org/10.1007/s12272-016-0820-y.

    Article  CAS  Google Scholar 

  11. Kim J, Bae JS. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediat Inflamm. 2016;2016:6058147. https://doi.org/10.1155/2016/6058147.

    Article  CAS  Google Scholar 

  12. Wu X, Ma Y, Cheng J, Li X, Zheng H, Jiang L, et al. TIPE1 function as a prognosis predictor and negative regulator of lung cancer. Oncotarget. 2017;8(45):78496–506. https://doi.org/10.18632/oncotarget.19655.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang Z, Liang X, Gao L, Ma H, Liu X, Pan Y, et al. TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells. Oncogene. 2015;34(20):2566–74. https://doi.org/10.1038/onc.2014.208.

    Article  CAS  PubMed  Google Scholar 

  14. Liu W, Chen Y, Xie H, Guo Y, Ren D, Li Y, et al. TIPE1 suppresses invasion and migration through down-regulating Wnt/beta-catenin pathway in gastric cancer. J Cell Mol Med. 2017. https://doi.org/10.1111/jcmm.13362.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT method. Methods (San Diego, Calif). 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.1262.

    Article  CAS  Google Scholar 

  16. Dai L, Cui X, Zhang X, Cheng L, Liu Y, Yang Y, et al. SARI inhibits angiogenesis and tumor growth of human colon cancer through directly targeting ceruloplasmin. Nat Commun. 2016;7:11996. https://doi.org/10.1038/ncomms11996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–20. https://doi.org/10.1016/j.it.2016.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xiao Q, Zhang X, Wu Y, Yang Y. Inhibition of macrophage polarization prohibits growth of human osteosarcoma. Tumor Biol. 2014;35(8):7611–6. https://doi.org/10.1007/s13277-014-2005-y.

    Article  CAS  Google Scholar 

  19. Segaliny AI, Mohamadi A, Dizier B, Lokajczyk A, Brion R, Lanel R, et al. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int J Cancer. 2015;137(1):73–85. https://doi.org/10.1002/ijc.29376.

    Article  CAS  PubMed  Google Scholar 

  20. Kimura Y, Sumiyoshi M, Baba K. Antitumor and antimetastatic activity of synthetic hydroxystilbenes through inhibition of lymphangiogenesis and M2 macrophage differentiation of tumor-associated macrophages. Anticancer Res. 2016;36(1):137–48.

    CAS  PubMed  Google Scholar 

  21. Han Q, Shi H, Liu F. CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma. Int Immunopharmacol. 2016;34:101–6. https://doi.org/10.1016/j.intimp.2016.01.023.

    Article  CAS  PubMed  Google Scholar 

  22. Wolfs IM, Donners MM, de Winther MP. Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb Haemost. 2011;106(5):763–71. https://doi.org/10.1160/th11-05-0320.

    Article  CAS  PubMed  Google Scholar 

  23. Zou K, Wang Y, Hu Y, Zheng L, Xu W, Li G. Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment. Tumor Biol. 2017;39(3):1010428317695962. https://doi.org/10.1177/1010428317695962.

    Article  Google Scholar 

  24. Hultgren EM, Patrick ME, Evans RL, Stoos CT, Egland KA. SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer. PLoS One. 2017;12(5):e0177089. https://doi.org/10.1371/journal.pone.0177089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen Q, Sun W, Liao Y, Zeng H, Shan L, Yin F, et al. Monocyte chemotactic protein-1 promotes the proliferation and invasion of osteosarcoma cells and upregulates the expression of AKT. Mol Med Rep. 2015;12(1):219–25. https://doi.org/10.3892/mmr.2015.3375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The present study was supported by Natural Science Foundation of Jiangsu Province (BK20161069).

Author information

Author notes

  1. P. Chen and J. Zhou contributed equally.

Authors and Affiliations

  1. Department of Orthopedics, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Nanjing, 211189, China

    P. Chen

  2. Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China

    J. Zhou, J. Li, Q. Zhang & Q. Zuo

Authors
  1. P. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Q. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q. Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PC and JCZ were involved in the acquisition of the data. JML and QZ were involved in the analysis and interpretation of the data. QZ was involved in the conception and design of the present study.

Corresponding author

Correspondence to Q. Zuo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, P., Zhou, J., Li, J. et al. TIPE1 suppresses osteosarcoma tumor growth by regulating macrophage infiltration. Clin Transl Oncol 21, 334–341 (2019). https://doi.org/10.1007/s12094-018-1927-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-018-1927-z

Keywords

Search

Navigation