Skip to main content

Advertisement

SpringerLink
Log in

Angiopoietin-2 as a Prognostic Factor in Patients with Incurable Stage IV Colorectal Cancer

  • Original Research
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Purpose

Angiopoietin (Ang), a ligand of the endothelium-specific receptor Tie-2 system, is associated with tumor growth and progression that depend on angiogenesis. The present study aimed to investigate the predictive potential of angiopoietin factors in incurable stage IV colorectal cancer (CRC) patients who have undergone primary tumor resection.

Methods

The study included 40 consecutive patients with incurable stage IV CRC who underwent primary tumor resection at our hospital between 2011 and 2015. Patients were divided into subgroups of low and high Ang-1, Ang-2, and Tie-2. Patient age and sex, tumor location, TNM stages, vascular invasion, chemotherapy, and overall survival were assessed.

Results

The cut-off values of Ang-1, Ang-2, and Tie-2 were 0.4, 1.8, and 15.0 ng/mL, respectively. Overall survival was significantly longer in the low Ang-2 group than in the high Ang-2 group. High Ang-2 levels were associated with age, N stage, and chemotherapy. Immunofluorescent staining of Ang-2 revealed that endothelial cells and cancer cells expressed Ang-2 in each case.

Conclusions

Our findings suggest that the serum Ang-2 level is associated with disease progression and is an important predictor of mortality in incurable stage IV CRC patients. Thus, it may be a useful prognostic biomarker in these patients.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ROC:

Receiver operating characteristic

Ang:

Angiopoietin

CRC:

Colorectal cancer

PS:

Performance status

ASA:

American Society of Anesthesiologists

References

  1. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6.

    Article  CAS  Google Scholar 

  2. Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010;10:575–85.

    Article  CAS  Google Scholar 

  3. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277:55–60.

    Article  CAS  Google Scholar 

  4. Ahmad SA, Liu W, Jung YD, et al. Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma A possible mechanism for the initiation of angiogenesis. Cancer. 2001;92:1138–43.

    Article  CAS  Google Scholar 

  5. Engin H, Ustundag Y, Tekin IO, Gokmen A, Ertop S, Ilikhan SU. Plasma concentrations of angiopoietin-1, angiopoietin-2 and Tie-2 in colon cancer. Eur Cytokine Netw. 2012;23:68–71.

    Article  CAS  Google Scholar 

  6. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.

    Article  Google Scholar 

  7. Benson AB 3rd, Bekaii-Saab T, Chan E, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2013;11:141–52.

    Article  CAS  Google Scholar 

  8. Sallinen H, Heikura T, Koponen J, et al. Serum angiopoietin-2 and soluble VEGFR-2 levels predict malignancy of ovarian neoplasm and poor prognosis in epithelial ovarian cancer. BMC Cancer. 2014;14:696.

    Article  Google Scholar 

  9. Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer. 2010;103:1407–14.

    Article  CAS  Google Scholar 

  10. van der Wal GE, Gouw AS, Kamps JA, Moorlag HE, Bulthuis ML, Molema G, et al. Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil. Ann Surg. 2012;255:86–94.

    Article  Google Scholar 

  11. Ahmad SA, Liu WB, Jung YD, Fan F, Reinmuth N, Bucana CD, et al. Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma—a possible mechanism for the initiation of angiogenesis. Cancer. 2001;92:1138–43.

    Article  CAS  Google Scholar 

  12. Eklund L, Olsen BR. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res. 2006;312:630–41.

    Article  CAS  Google Scholar 

  13. Hong S, Jung HI, Ahn TS, Kim HJ, Lee KT, Baek MJ, et al. Expressions and clinical significances of angiopoietin-1, angiopoietin-2, and Tie-2 receptor in patients with colorectal cancer. Ann Coloproctol. 2017;33:9–15.

    Article  Google Scholar 

  14. Gerber H-P, Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med. 2002;81:20–31.

    Article  Google Scholar 

  15. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.

    Article  CAS  Google Scholar 

  16. Hashizume H, Falcon BL, Kuroda T, et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 2010;70:2213–23.

    Article  CAS  Google Scholar 

  17. Bohn KA, Adkins CE, Nounou MI, Lockman PR. Inhibition of VEGF and angiopoietin-2 to reduce brain metastases of breast cancer burden. Front Pharmacol. 2017;8:193.

    Article  Google Scholar 

  18. Isambert N, Elez E, Zanetta S, Matos I, Nazabadioko S, Xue WQ (2018) A phase I, open-label dose-escalation trial of weekly (qw) BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking nanobody, in patients (pts) with advanced/metastatic solid tumors. J Clin Oncol 36.

  19. Schmittnaegel M, Rigamonti N, Kadioglu E, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017;9:eaak9670.

    Article  Google Scholar 

  20. Wu X, Giobbie-Hurder A, Liao X, Connelly C, Connolly EM, Li J, et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunol Res. 2017;5:17–28.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science Wakate Grant 16K09821 and 19K18104 (to S.M.)

Author information

Authors and Affiliations

  1. Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Shinya Munakata, Takae Ueyama, Haruna Ishihara, Hiromitsu Komiyama, Ryoichi Tsukamoto, Masaya Kawai, Makoto Takahashi, Yutaka Kojima, Yuichi Tomiki & Kazuhiro Sakamoto

Authors
  1. Shinya Munakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takae Ueyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haruna Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiromitsu Komiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryoichi Tsukamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masaya Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Makoto Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yutaka Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuichi Tomiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazuhiro Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design: S.M. Data acquisition: S.M., T.U., H.I., H.K., R.T., M.K., M.T., Y.K., Y.T., K.S. Analysis and interpretation of data: S.M. Drafting of the manuscript: S.M. Critical revision of the manuscript: S.M.

Corresponding author

Correspondence to Shinya Munakata.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Ethical Approval

This study was performed in accordance with the ethical standards of the Committee on Human Experimentation of our institution. All procedures were followed in accordance with the current revision of Helsinki Declaration.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Munakata, S., Ueyama, T., Ishihara, H. et al. Angiopoietin-2 as a Prognostic Factor in Patients with Incurable Stage IV Colorectal Cancer. J Gastrointest Canc 52, 237–242 (2021). https://doi.org/10.1007/s12029-020-00392-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-020-00392-1

Keywords

Search

Navigation