Skip to main content

Advertisement

Log in

Plasma levels of angiostatin and endostatin remain unchanged for the first 3 weeks after colorectal cancer surgery

  • Published:
Surgical Endoscopy Aims and scope Submit manuscript

Abstract

Introduction

Angiostatin and endostatin are endogenous inhibitors of angiogenesis with anticancer effects. After minimally invasive colorectal resection (MICR), blood levels of the proangiogenic factors vascular endothelial growth factor (VEGF) and angiopoetin 2 (Ang-2) are elevated for 2–4 weeks. Also, postoperative human plasma from weeks 2 and 3 after MICR has been shown to stimulate endothelial cell proliferation and migration, which are critical to angiogenesis. This proangiogenic state may stimulate tumor growth early after MICR. Surgery’s impact on angiostatin and endostatin is unknown. This study’s purpose is to determine perioperative plasma levels of these two proteins in colorectal cancer (CRC) patients undergoing MICR.

Methods

Endostatin levels were assessed in 34 CRC patients and angiostatin levels in 30 CRC patients. Blood samples were taken preoperatively and on postoperative day (POD) 1 and 3 in all patients; in a subset, samples were taken between POD 7 and 20. The late samples were bundled into 7-day blocks (POD 7–13, POD 14–20) and considered as single time points. Angiostatin and endostatin plasma levels were determined via enzyme-linked immunosorbent assay (ELISA) in duplicate. Wilcoxon signed-rank test and Student’s t test were used to analyze endostatin and angiostatin data, respectively. Significance was set at P < 0.0125 (after Bonferroni correction).

Results

There was a significant decrease in median plasma endostatin levels on POD 1, which returned to the preoperative level by POD 3. There was no significant difference between pre- and postoperative plasma angiostatin levels.

Conclusions

MICR has a very transient impact on plasma levels of endostatin and no impact on angiostatin during the first 21 days following surgery. Thus, angiostatin and endostatin do not likely contribute to or inhibit the persistent proangiogenic changes noted after MICR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Bird NC, Mangnall D, Majeed AW (2006) Biology of colorectal liver metastases: a review. J Surg Oncol 94:68–80

    Article  PubMed  CAS  Google Scholar 

  3. Allendorf JD, Bessler M, Horvath KD, Marvin MR, Laird DA, Whelan RL (1998) Increased tumor establishment and growth after open vs. laparoscopic bowel resection in mice. Surg Endosc 12:1035–1038

    Article  PubMed  CAS  Google Scholar 

  4. Leather AJ, Gallegos NC, Kocjan G, Savage F, Smales CS, Hu W, Boulos PB, Northover JM, Phillips RK (1993) Detection and enumeration of circulating tumour cells in colorectal cancer. Br J Surg 80:777–780

    Article  PubMed  CAS  Google Scholar 

  5. Shantha Kumara HMC, Feingold D, Kalady M, Dujovny N, Senagore A, Hyman N, Cekic V, Whelan RL (2009) Colorectal resection is associated with persistent proangiogenic plasma protein changes: postoperative plasma stimulates in vitro endothelial cell growth, migration, and invasion. Ann Surg 249(6):973–977

    Article  PubMed  Google Scholar 

  6. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  PubMed  CAS  Google Scholar 

  7. Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979

    Article  PubMed  CAS  Google Scholar 

  8. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328

    Article  PubMed  Google Scholar 

  9. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    Article  PubMed  Google Scholar 

  10. O’Reilly MS, Holmgren L, Chen C, Folkman J (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2:689–692

    Article  PubMed  Google Scholar 

  11. Sund M, Hamano Y, Sugimoto H, Sudhakar A, Soubasakos M, Yerramalla U, Benjamin LE, Lawler J, Kieran M, Shah A, Kalluri R (2005) Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc Natl Acad Sci USA 102:2934–2939

    Article  PubMed  CAS  Google Scholar 

  12. Sun Y, Wang J, Liu Y, Song X, Zhang Y, Li K, Zhu Z, Zhou Q, You L, Yao C (2005) Results of phase III trial of rh-endostatin (YH-16) in advanced non-small cell lung cancer (NSCLC) patients. J Clin Oncol 23, No 16S (June 1 Supplement) 7138

  13. Sharma MR, Tuszynski GP, Sharma MC (2004) Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J Cell Biochem 91:398–409

    Article  PubMed  CAS  Google Scholar 

  14. Shichiri M, Hirata Y (2001) Antiangiogenic signals by endostatin. FASEB J 15:1044–1053

    Article  PubMed  CAS  Google Scholar 

  15. Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, Ramchandran R, Pestell R, Sukhatme VP (2002) Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J Biol Chem 277:16464–16469

    Article  PubMed  CAS  Google Scholar 

  16. Troyanovsky B, Levchenko T, Mansson G, Matvijenko O, Holmgren L (2001) Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J Cell Biol 152:1247–1254

    Article  PubMed  CAS  Google Scholar 

  17. MacDonald NJ, Shivers WY, Narum DL, Plum SM, Wingard JN, Fuhrmann SR, Liang H, Holland-Linn J, Chen DH, Sim BK (2001) Endostatin binds tropomyosin: a potential modulator of the antitumor activity of endostatin. J Biol Chem 276:25190–25196

    Article  PubMed  CAS  Google Scholar 

  18. Dixelius J, Cross Mi, Matsumoto T, Sasaki T, Claseson-Welsh L (2002) Endostatin regulates endothelial cell adhesion and cytoskeletal organization. Cancer Res 62:1944–1947

    PubMed  CAS  Google Scholar 

  19. Chen YH, Wu HL, Li C, Huang YH, Chiang CW, Wu MP, Wu LW (2006) Anti-angiogenesis mediated by angiostatin K1–3, K1–4 and K1–4.5. Involvement of p53, FasL, AKT and mRNA deregulation. Thromb Haemost 95:668–677

    PubMed  CAS  Google Scholar 

  20. Gupta N, Nodzenski E, Khodarev NN, Yu J, Khorasani L, Beckett MA, Kufe DW, Weichselbaum RR (2001) Angiostatin effects on endothelial cells mediated by ceramide and RhoA. EMBO Rep 2:536–540

    PubMed  CAS  Google Scholar 

  21. Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engström A, Timpl R, Welsh M, Claesson-Welsh L (2000) Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95:3403–3411

    PubMed  CAS  Google Scholar 

  22. Kang HY, Shim D, Kang SS, Chang SI, Kim HY (2006) Protein kinase B inhibits endostatin-induced apoptosis in HUVECs. J Biochem Mol Biol 39:97–104

    Article  PubMed  CAS  Google Scholar 

  23. Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP (1999) Endostatin induces endothelial cell apoptosis. J Biol Chem 274:11721–11726

    Article  PubMed  CAS  Google Scholar 

  24. Feldman AL, Alexander HR Jr, Bartlett DL, Kranda KC, Miller MS, Costouros NG, Choyke PL, Libutti SK, Feldman AL (2001) A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases. Ann Surg Oncol 8:741–745

    Article  PubMed  CAS  Google Scholar 

  25. Shaarawy M, EI-Sharkawy SA (2001) Biomarker of intrinsic angiogenic and anti-angiogenic activity in patients with endometrial hyperplasia and endometrial cancer. Acta Oncol 40:513–518

    Article  PubMed  CAS  Google Scholar 

  26. Feldman AL, Alexander HR Jr, Yang JC, Linehan WM, Eyler RA, Libutti MS (2002) Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma. Cancer 95:1637–1643

    Article  PubMed  CAS  Google Scholar 

  27. Zhao J, Yan F, Ju H, Tang J, Qin J (2004) Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer. Cancer Lett 204:87–95

    Article  PubMed  CAS  Google Scholar 

  28. Bjornland K, Buo L, Scott H, Konttinen Y, Johansen HT, Aasen AO (1998) Polymorphonuclear elastase in human colorectal carcinoma. Int J Oncol 12:535–540

    PubMed  CAS  Google Scholar 

  29. Feldman AL, Tamarkin L, Paciotti GF, Simpson BW, Linehan WM, Yang JC, Fogler WE, Turner EM, Alexander HR Jr, Libutti SK (2000) Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer. Clin Cancer Res 6:4628–4634

    PubMed  CAS  Google Scholar 

  30. Kim YM, Hwang S, Kim YM, Pyun BJ, Kim TY, Lee ST, Gho YS, Kwon YG (2002) Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J Biol Chem 277:27872–27879

    Article  PubMed  CAS  Google Scholar 

  31. Shantha Kumara HMC, Kirman I, Feingold D, Cekic V, Nasar A, Arnell T, Balik E, Hoffman A, Baxter R, Conte S, Whelan RL (2009) Perioperative GMCSF limits the proangiogenic plasma protein changes associated with colorectal cancer resection. Eur J Surg Oncol 35(3):295–301

    PubMed  CAS  Google Scholar 

  32. Wu FP, Sietses C, von Blomberg BM, van Leeuwen PA, Meijer S, Cuesta MA (2003) Systemic and peritoneal inflammatory response after laparoscopic or conventional colon resection in cancer patients: a prospective, randomized trial. Dis Colon Rectum 46:147–155

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosures

HMC Shantha Kumara, Samer T Tohme, Xiaohong Yan, Abu Nasar, Anthony J Senagore, Matthew F Kalady, Neil Hyman, Ik Y Kim, and Richard L Whelan have no conflicts of interest or financial ties to disclosure.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard L. Whelan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shantha Kumara, H.M.C., Tohme, S.T., Yan, X. et al. Plasma levels of angiostatin and endostatin remain unchanged for the first 3 weeks after colorectal cancer surgery. Surg Endosc 25, 1939–1944 (2011). https://doi.org/10.1007/s00464-010-1491-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00464-010-1491-2

Keywords

Navigation