Skip to main content

Advertisement

SpringerLink
Log in

Minimally invasive colon resection for malignant colonic conditions is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery

  • Published:
Surgical Endoscopy Aims and scope Submit manuscript

Abstract

Introduction

Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2–4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer.

Methods

Forty-five patients were studied; blood samples were taken from all patients preoperatively (preop) and on postoperative days (POD) 1 and 3; in most a fourth sample was drawn between POD 7–30. Late samples were bundled into two time points: POD 7–13 and POD 14–30. sVEGFR1 and sVEGFR2 levels were measured via ELISA. sVEGFR2 data are reported as mean ± SD and were assessed with the paired samples t test. sVEGFR1 data were not normally distributed. They are reported as median and 95% confidence interval (CI) and were assessed with the Wilcoxon signed-Rank test (p < 0.05).

Results

Preoperatively, the mean plasma sVEGFR2 level (7583.9 pg/ml) was greater than the sVEGFR1 result (98.3 pg/ml). Compared with preop levels, sVEGFR2 levels were significantly lower on POD 1 (6068.2 pg/ml, ±2034.5) and POD 3 (6227.6 pg/ml, ±2007.0), whereas sVEGFR1 levels were significantly greater on POD 1 (237.5 pg/ml; 95% CI, 89.6–103.5), POD 3 (200.2 pg/ml; 95% CI, 159–253), and POD 7−13 (102.9 pg/ml; 95% CI, 189.7–253). No differences were found on POD 7–13 for sVEGFR2 or POD 14–30 for either protein.

Conclusions

sVEGFR2 values decreased and sVEGFR1 levels increased early after MICR; sVEGFR2 changes dominate due to their much larger magnitude. The net result is less plasma VEGF bound by soluble receptors and more plasma VEGF available to bind to ECs early after surgery.

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

Similar content being viewed by others

References

  1. Kirman I, Belizon A, Balik E, Feingold D, Arnell T, Horst P, Kumara S, Cekic V, Jain S, Nasar A, Whelan RL (2007) Perioperative sargramostim (recombinant human GM-CSF) induces an increase in the level of soluble VEGFR1 in colon cancer patients undergoing minimally invasive surgery. Eur J Surg Oncol 33:1169–1176

    CAS  PubMed  Google Scholar 

  2. Mels AK, Statius Muller MG, van Leeuwen PA, von Blomberg BM, Scheper RJ, Cuesta MA, Beelen RH, Meijer S (2001) Immune-stimulating effects of low-dose perioperative recombinant granulocyte-macrophage colony-stimulating factor in patients operated on for primary colorectal carcinoma. Br J Surg 88:539–544

    Article  CAS  PubMed  Google Scholar 

  3. Shantha Kumara HMC, Kirman I, Feingold D, Cekic V, Nasar A, Arnell T, Balik E, Hoffman A, Baxter R, Conte S, Whelan RL (2008) Perioperative GMCSF limits the proangiogenic plasma protein changes associated with colorectal cancer resection. Eur J Surg Oncol 35:295–301

    PubMed  Google Scholar 

  4. 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  CAS  PubMed  Google Scholar 

  5. Carter JJ, Feingold DL, Kirman I, Oh A, Wildbrett P, Asi Z, Fowler R, Huang E, Whelan RL (2003) Laparoscopic-assisted cecectomy is associated with decreased formation of postoperative pulmonary metastases compared with open cecectomy in a murine model. Surgery 134:432–436

    Article  PubMed  Google Scholar 

  6. Belizon A, Balik E, Horst P, Feingold D, Arnell T, Azarani T, Cekic V, Skitt R, Kumara S, Whelan RL (2008) Persistent elevation of plasma vascular endothelial growth factor levels during the first month after minimally invasive colorectal resection. Surg Endosc 22:287–297

    Article  CAS  PubMed  Google Scholar 

  7. Shantha Kumara HMC, Hoffman A, Kim IY, Feingold D, Dujovny N, Kallady M, Luchtefeld M, Whelan RL (2009) Colorectal resection, both open and laparoscopic- assisted, in patients with benign indications is associated with proangiogenic changes in plasma angiopoietin 1 and 2 levels. Surg Endosc 23:409–415

    Article  CAS  PubMed  Google Scholar 

  8. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  CAS  PubMed  Google Scholar 

  9. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  CAS  PubMed  Google Scholar 

  10. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22

    CAS  PubMed  Google Scholar 

  11. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    Article  CAS  PubMed  Google Scholar 

  12. Bellamy WT, Richter L, Frutiger Y, Grogan TM (1999) Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 59:728–733

    CAS  PubMed  Google Scholar 

  13. Decaussin M, Sartelet H, Robert C, Moro D, Claraz C, Brambilla C, Brambilla E (1999) Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival. J Pathol 188:369–377

    Article  CAS  PubMed  Google Scholar 

  14. Ferrer FA, Miller LJ, Lindquist R, Kowalczyk P, Laudone VP, Albertsen PC, Kreutzer DL (1999) Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology 54:567–572

    Article  CAS  PubMed  Google Scholar 

  15. Folkman J (1997) Addressing tumor blood vessels. Nat Biotechnol 15:510

    Article  CAS  PubMed  Google Scholar 

  16. Lacal PM, Failla CM, Pagani E, Odorisio T, Schietroma C, Falcinelli S, Zambruno G, D’Atri S (2000) Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 115:1000–1007

    Article  CAS  PubMed  Google Scholar 

  17. Price DJ, Miralem T, Jiang S, Steinberg R, Avraham H (2001) Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ 2:129–135

    Google Scholar 

  18. George DJ, Halabi S, Shepard TF, Vogelzang NJ, Hayes DF, Small EJ, Kantoff PW (2001) Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 7:1932–1936

    CAS  PubMed  Google Scholar 

  19. Hyodo I, Doi T, Endo H, Hosokawa Y, Nishikawa Y, Tanimizu M, Jinno K, Kotani Y (1998) Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 34:2041–2045

    Article  CAS  PubMed  Google Scholar 

  20. Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G, Simopoulos C, Karatzas G (2002) Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236:37–42

    Article  PubMed  Google Scholar 

  21. Karayiannakis AJ, Syrigos KN, Zbar A, Baibas N, Polychronidis A, Simopoulos C, Karatzas G (2002) Clinical significance of preoperative serum vascular endothelial growth factor levels in patients with colorectal cancer and the effect of tumor surgery. Surgery 131:548–555

    Article  PubMed  Google Scholar 

  22. Takeda A, Shimada H, Imaseki H, Okazumi S, Natsume T, Suzuki T, Ochiai T (2000) Clinical significance of serum vascular endothelial growth factor in colorectal cancer patients: correlation with clinicopathological factors and tumor markers. Oncol Rep 7:333–338

    CAS  PubMed  Google Scholar 

  23. De Vita F, Orditura M, Lieto E, Infusino S, Morgillo F, Martinelli E, Castellano P, Romano C, Ciardiello F, Catalano G, Pignatelli C, Galizia G (2004) Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer 100:270–278

    Article  PubMed  Google Scholar 

  24. Hormbrey E, Han C, Roberts A, McGrouther DA, Harris AL (2003) The relationship of human wound vascular endothelial growth factor (VEGF) after breast cancer surgery to circulating VEGF and angiogenesis. Clin Cancer Res 9:4332–4339

    CAS  PubMed  Google Scholar 

  25. Karayiannakis AJ, Zbar A, Polychronidis A, Simopoulos C (2003) Serum and drainage fluid vascular endothelial growth factor levels in early surgical wounds. Eur Surg Res 35:492–496

    Article  CAS  PubMed  Google Scholar 

  26. Belizon A, Balik E, Feingold DL, Bessler M, Arnell TD, Forde KA, Horst PK, Jain S, Cekic V, Kirman I, Whelan RL (2006) Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods. Ann Surg 244:792–798

    Article  PubMed  Google Scholar 

  27. Wu FP, Westphal JR, Hoekman K, Mels AK, Statius Muller MG, de Waal RW, Beelen RH, van Leeuwen PA, Meijer S, Cuesta MA (2004) The effects of surgery, with or without rhGM-CSF, on the angiogenic profile of patients treated for colorectal carcinoma. Cytokine 25:68–72

    Article  CAS  PubMed  Google Scholar 

  28. Matsumoto T, Claesson-Welsh L (2001) VEGF receptor signal transduction. Sci STKE 2001 112:RE21

    Google Scholar 

  29. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  30. Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271:58–65

    Article  CAS  PubMed  Google Scholar 

  31. Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MA, Rafii S (2001) Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci U S A 98:10857–10862

    Article  CAS  PubMed  Google Scholar 

  32. Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 106:511–521

    Article  CAS  PubMed  Google Scholar 

  33. Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, Somcio RJ, Wu Y, Hooper A, Hicklin DJ, Ellis LM (2005) Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24:2647–2653

    Article  CAS  PubMed  Google Scholar 

  34. Hayashibara T, Yamada Y, Miyanishi T, Mori H, Joh T, Maeda T, Mori N, Maita T, Kamihira S, Tomonaga M (2001) Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion. Clin Cancer Res 7:2719–2726

    CAS  PubMed  Google Scholar 

  35. Lamszus K, Ulbricht U, Matschke J, Brockmann MA, Fillbrandt R, Westphal M (2003) Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 9:1399–1405

    CAS  PubMed  Google Scholar 

  36. Toi M, Bando H, Ogawa T, Muta M, Hornig C, Weich HA (2002) Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer. Int J Cancer 98:14–18

    Article  CAS  PubMed  Google Scholar 

  37. Yamaguchi T, Bando H, Mori T, Takahashi K, Matsumoto H, Yasutome M, Weich H, Toi M (2007) Over expression of soluble vascular endothelial growth factor receptor 1 in colorectal cancer: Association with progression and prognosis. Cancer Sci 98:405–410

    Article  CAS  PubMed  Google Scholar 

  38. Aref S, Sakrana M, Hafez AA, Hamdy M (2005) Soluble VEGF/sFLt1 ratio is an independent predictor of AML patient out come. Hematology 10:131–134

    Article  CAS  PubMed  Google Scholar 

  39. Ilhan N, Deveci F (2004) Functional significance of vascular endothelial growth factor and its receptor (receptor-1) in various lung cancer types. Clin Biochem 37:840–845

    Article  CAS  PubMed  Google Scholar 

  40. Kumar H, Heer K, Greenman J, Kerin MJ, Monson JR (2002) Soluble FLT-1 is detectable in the sera of colorectal and breast cancer patients. Anticancer Res 22:1877–1880

    CAS  PubMed  Google Scholar 

  41. Taoka T, Iwasaki S, Uchida H, Fukusumi A, Kichikawa K, Nakagawa H, Takayama K, Sakamoto M, Ohishi H (2000) Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ. Cancer Res 60:2169–2177

    Google Scholar 

  42. Hu Q, Dey AL, Yang Y, Shen Y, Jilani IB, Estey EH, Kantarjian HM, Giles FJ, Albitar M (2004) Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes. Cancer 100:1884–1891

    Article  CAS  PubMed  Google Scholar 

  43. Jain RK, Duda DG, Clark JW, Loeffler JS (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24–40

    Article  CAS  PubMed  Google Scholar 

  44. Shantha Kumara HMC, Cabot CJ, Hoffman A, Luchtefeld M, Kalady M, Hyman N, Feingold D, Baxter R, Whelan RL (2009) Minimally invasive colon resection is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery. Surg Endosc [Epub ahead of print]

  45. Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, Girardi L, Yurt R, Himel H, Rafii S (2001) Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 88:167–174

    CAS  PubMed  Google Scholar 

  46. Kitsukawa T, Shimono A, Kawakami A, Kondoh H, Fujisawa H (1995) Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121:4309–4318

    CAS  PubMed  Google Scholar 

  47. Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M (2000) Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J 14:2532–2539

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Colon and Rectal Surgery, Department of Surgery, New York-Presbyterian Hospital-Columbia Campus, 177 Fort Washington Avenue, New York, NY, 10032, USA

    H. M. C. Shantha Kumara, J. C. Cabot, A. Hoffman, D. Feingold, R. Baxter & R. L. Whelan

  2. Division of Colon and Rectal Surgery, Ferguson Clinic, 4100, Lake Dr. SE, Suite 205, Grand Rapids, MI, 49546, USA

    M. Luchtefeld

  3. Department of Colorectal Surgery, Cleveland Clinic, 9500, Euclid Avenue, A30, Cleveland, OH, 44195, USA

    M. F. Kalady

  4. Department of Surgery, Fletcher 465, University of Vermont, College of Medicine, Burlington, VT, 05401, USA

    N. Hyman

Authors
  1. H. M. C. Shantha Kumara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. C. Cabot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Luchtefeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. F. Kalady
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Feingold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Baxter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. L. Whelan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. L. Whelan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shantha Kumara, H.M.C., Cabot, J.C., Hoffman, A. et al. Minimally invasive colon resection for malignant colonic conditions is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery. Surg Endosc 24, 283–289 (2010). https://doi.org/10.1007/s00464-009-0575-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00464-009-0575-3

Keywords

Search

Navigation