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Plasma levels of angiopoietin-like protein 4 (ANGPTL4) are significantly lower preoperatively in colorectal cancer patients than in cancer-free patients and are further decreased during the first month after minimally invasive colorectal resection

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Abstract

Background

Surgery has been associated with proangiogenic plasma protein changes that may promote tumor growth. Angiopoietin-like protein 4 (ANGPTL4) is expressed by endothelial cells and other tissues in response to hypoxia. Both intact ANGPTL4 and its partly degraded C-terminal fragment may promote tumor angiogenesis. This study had two purposes: to measure and compare preoperative plasma ANGPTL4 levels in patients with colorectal cancer (CRC) and benign colorectal disease (BCD) and to determine plasma levels after minimally invasive colorectal resection (MICR) for CRC.

Methods

Plasma was obtained from an IRB-approved plasma/data bank. Preoperative plasma ANGPTL4 levels were measured for CRC and BCD patients, but postoperative levels were determined only for CRC patients for whom a preoperative, a postoperative day (POD) 3, and at least one late postoperative sample (POD 7–55) were available. Late samples were bundled into four time blocks and considered as single time points. ANGPTL4 levels (mean ± SD) were measured via ELISA and compared (significance, p < 0.01 after Bonferroni correction).

Results

Eighty CRC (71  % colon, 29  % rectal) and 60 BCD (62  % diverticulitis, 38  % adenoma) patients were studied. The mean preoperative plasma ANGPTL4 level in CRC patients (247.2 ± 230.7 ng/ml) was lower than the BCD group result (330.8 ± 239.0 ng/ml, p = 0.01). There was an inverse relationship between plasma levels and advanced CRC as judged by three criteria. In regard to the postoperative CRC analysis, the “n” for each time point varied: lower plasma levels (p < 0.001) were noted on POD 3 (161.4 ± 140.4 ng/ml, n = 80), POD 7–13 (144.6 ± 134.5 ng/ml, n = 46), POD 14–20 (139.0 ± 117.8 ng/ml, n = 27), POD 21–27 (138.9 ± 202.4, n = 20), and POD 28–55 (160.1 ± 179.0, n = 42) when compared to preoperative results.

Conclusion

CRC is associated with lower preoperative plasma ANGPTL4 levels compared with BCD, and the levels may vary inversely with disease severity. After MICR for CRC, levels are significantly lower for over a month compared with the preoperative level; the cause for this persistent decrease is unclear. The implications of both the lower preoperative level and the persistently decreased postoperative levels are unclear. Further studies are needed.

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References

  1. Weese JL, Ottery FD, Emoto SE (1986) Do operations facilitate tumor growth? An experimental model in rats. Surgery 100(2):273–277

    PubMed  CAS  Google Scholar 

  2. Allendorf JD, Bessler M, Kayton ML, Oesterling SD, Treat MR, Nowygrod R (1995) Increased tumor establishment and growth after laparotomy vs. laparoscopy in a murine model. Arch Surg 130(6):649–653

    Article  PubMed  CAS  Google Scholar 

  3. Allendorf JD, Bessler M, Horvath KD, Marvin MR, Laird DA, Whelan RL (1999) Increased tumor establishment and growth after open vs. laparoscopic surgery in mice may be related to difference in postoperative T-cell function. Surg Endosc 13(3):233–235

    Article  PubMed  CAS  Google Scholar 

  4. Wind J, Tuynman JB, Tibbe AG, Swennenhuis JF, Richel DJ, van Berge Henegouwen MI, Bemelman WA (2009) Circulating tumour cells during laparoscopic and open surgery for primary colonic cancer in portal and peripheral blood. Eur J Surg Oncol 35(9):942–950

    Article  PubMed  CAS  Google Scholar 

  5. Lennard TW, Shenton BK, Borzotta A, Donnelly PK, White M, Gerrie LM, Proud G, Taylor RM (1985) The influence of surgical operations on components of the human immune system. Br J Surg 72:771–776

    Article  PubMed  CAS  Google Scholar 

  6. Eggermont AM, Steller EP, Sugerbaker PH (1987) Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin-2 and lymphokine-activated killer cells. Surgery 102:71–78

    PubMed  CAS  Google Scholar 

  7. Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175(3):409–416

    Article  PubMed  CAS  Google Scholar 

  8. 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  PubMed  CAS  Google Scholar 

  9. Shantha Kumara HMC, Hoffman A, Kim IY, Feingold D, Dujovny N, Kalady 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(2):409–415

    Article  PubMed  CAS  Google Scholar 

  10. Shantha Kumara HMC, Cabot JC, Yan X, Herath SA, Luchtefeld M, Kalady MF, Feingold DL, Baxter R, Whelan RL (2011) Minimally invasive colon resection is associated with a persistent increase in plasma PlGF levels following cancer resection. Surg Endosc 25(7):2153–2158

    Article  PubMed  CAS  Google Scholar 

  11. 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 

  12. Shantha Kumara HMC, Tohme ST, Herath SA, Yan X, Senagore AJ, Nasar A, Kalady MF, Baxter R, Whelan RL (2012) Plasma soluble vascular adhesion molecule-1 levels are persistently elevated during the first month after colorectal cancer resection. Surg Endosc. doi:10.1007/s00464-011-2112-4

  13. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE-2 receptor, during embryonic angiogenesis. Cell 87:1171–1180

    Article  PubMed  CAS  Google Scholar 

  14. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science 277:55–60

    Article  PubMed  CAS  Google Scholar 

  15. Le Jan S, Le Meur N, Cazes A, Philippe J, Le Cunff M, Léger J, Corvol P, Germain S (2006) Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGF2BP3 in cancer. FEBS Lett 580:3395–3400

    Article  PubMed  Google Scholar 

  16. Le Jan S, Amy C, Cazes A, Monnot C, Lamandé N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P, Germain S (2003) Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 162:1521–1528

    Article  PubMed  Google Scholar 

  17. Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Müller M, Kersten S (2006) The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem 281(2):934–944

    Article  PubMed  CAS  Google Scholar 

  18. Cazes A, Galaup A, Chomel C, Bignon M, Bréchot N, Le Jan S, Weber H, Corvol P, Muller L, Germain S, Monnot C (2006) Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton. Circ Res 99:1207–1215

    Article  PubMed  CAS  Google Scholar 

  19. Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E, Mekid H, Mir LM, Opolon P, Corvol P, Monnot C, Germain S (2006) Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci 103(49):18721–18726

    Article  PubMed  CAS  Google Scholar 

  20. Chomel C, Cazes A, Faye C, Bignon M, Gomez E, Ardidie-Robouant C, Barret A, Ricard-Blum S, Muller L, Germain S, Monnot C (2009) Interaction of the coiled-coil domain with glycosaminoglycans protects angiopoietin-like 4 from proteolysis and regulates its antiangiogenic activity. FASEB J 23:940–949

    Article  PubMed  CAS  Google Scholar 

  21. Zhang H, Wong CC, Wei H et al (2012) HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31(14):1757–1770

    Article  PubMed  CAS  Google Scholar 

  22. Huang RL, Teo Z, Chong HC et al (2011) ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood 118(14):3990–4002

    Article  PubMed  CAS  Google Scholar 

  23. Kim SH, Park YY, Kim SW et al (2011) ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression. Cancer Res 71(22):7010–7020

    Article  PubMed  CAS  Google Scholar 

  24. Gudehithlu KP, Ahmed N, Wu H et al (2005) Antagonism of vascular endothelial growth factor results in microvessel attrition and disorganization of wound tissue. J Lab Clin Med 145(4):194–203

    Article  PubMed  CAS  Google Scholar 

  25. Karayiannakis AJ, Zbar A, Polychronidis A et al (2003) Serum and drainage fluid vascular endothelial growth factor levels in early surgical wounds. Eur Surg Res 35(6):492–496

    Article  PubMed  CAS  Google Scholar 

  26. Hormbrey E, Han C, Roberts A et 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(12):4332–4339

    PubMed  CAS  Google Scholar 

  27. Goh YY, Pal M, Chong HC et al (2010) Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing. J Biol Chem 285(43):32999–33009

    Article  PubMed  CAS  Google Scholar 

  28. Goh YY, Pal M, Chong HC et al (2010) Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration. Am J Pathol 177(6):2791–2803

    Article  PubMed  CAS  Google Scholar 

  29. Perdiguero EG, Galaup A, Durand M et al (2011) Alteration of developmental and pathological retinal angiogenesis in angptl4-deficient mice. J Biol Chem 286(42):36841–36851

    Article  PubMed  CAS  Google Scholar 

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Disclosures

H. M. C. Shantha Kumara, Daniel Kirchoff, S. A. Herath, Joon Ho Jang, Xiaohong Yan, M. Grieco, Vesna Cekic, and Richard L. Whelan have no conflicts of interest or financial ties to disclose.

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Authors and Affiliations

  1. Division of Colon and Rectal Surgery, Department of Surgery, St Luke-Roosevelt Hospital Center, Suite 7B, 425 West, 59th Street, New York, NY, 10019, USA

    H. M. C. Shantha Kumara, Daniel Kirchoff, Sajith A. Herath, Joon Ho Jang, Xiaohong Yan, Michael Grieco, Vesna Cekic & Richard L. Whelan

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

    Richard L. Whelan

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  1. H. M. C. Shantha Kumara
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Correspondence to Richard L. Whelan.

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Shantha Kumara, H.M.C., Kirchoff, D., Herath, S.A. et al. Plasma levels of angiopoietin-like protein 4 (ANGPTL4) are significantly lower preoperatively in colorectal cancer patients than in cancer-free patients and are further decreased during the first month after minimally invasive colorectal resection. Surg Endosc 26, 2751–2757 (2012). https://doi.org/10.1007/s00464-012-2269-5

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