Cell Stress and Chaperones

, Volume 16, Issue 1, pp 49–55 | Cite as

High levels of acute phase proteins and soluble 70 kDa heat shock proteins are independent and additive risk factors for mortality in colorectal cancer

  • Judit Kocsis
  • Tamás Mészáros
  • Balázs Madaras
  • Éva Katalin Tóth
  • Szilárd Kamondi
  • Péter Gál
  • Lilian Varga
  • Zoltán Prohászka
  • George Füst
Original Paper

Abstract

Recently, we reported that high soluble Hsp70 (sHsp70) level was a significant predictor of mortality during an almost 3-year-long follow-up period in patients with colorectal cancer. This association was the strongest in the group of <70-year-old female patients as well as in those who were in a less advanced stage of the disease at baseline. According to these observations, measurement of the serum level of sHsp70 is a useful, stage-independent prognostic marker in colorectal cancer, especially in patients without distant metastasis. Since many literature data indicated that measurement of C-reactive protein (CRP) and other acute phase proteins (APPs) may also be suitable for predicting the mortality of patients with colorectal cancer, it seemed reasonable to study whether the effect of sHsp70 and other APPs are related or independent. In order to answer this question, we measured the concentrations of CRP as well as of other complement-related APPs (C1 inhibitor, C3, and C9) along with that of the MASP-2 complement component in the sera of 175 patients with colorectal cancer and known levels of sHsp70, which have been used in our previous study. High (above median) levels of CRP, C1 esterase inhibitor (C1-INH), and sHsp70 were found to be independently associated with poor patient survival, whereas no such association was observed with the other proteins tested. According to the adjusted Cox proportional hazards analysis, the additive effect of high sHsp70, CRP, and C1-INH levels on the survival of patients exceeded that of high sHsp70 alone, with a hazard ratio (HR) of 2.83 (1.13–70.9). In some subgroups of patients, such as in females [HR 4.80 (1.07–21.60)] or in ≤70-year-old patients [HR 11.53 (2.78–47.70)], even greater differences were obtained. These findings indicate that the clinical mortality–prediction value of combined measurements of sHsp70, CRP, and C1-INH with inexpensive methods can be very high, especially in specific subgroups of patients with colorectal cancer.

Keywords

Colorectal cancer Heat shock proteins HSP70 Soluble HSP70 Surival CRP C3 C9 MASP-2 C1-inhbitor Acute phase proteins APP 

References

  1. Allin KH, Bojesen SE, Nordestgaard BG (2009) Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 27(13):2217CrossRefPubMedGoogle Scholar
  2. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539CrossRefPubMedGoogle Scholar
  3. Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348(10):891CrossRefPubMedGoogle Scholar
  4. Biro L, Varga L, Par A, Nemesanszky E, Csepregi A, Telegdy L, Ibranyi E, David K, Horvath G, Szentgyorgyi L, Nagy I, Dalmi L, Abonyi M, Fust G, Horanyi M (2000) Changes in the acute phase complement component and IL-6 levels in patients with chronic hepatitis C receiving interferon alpha-2b. Immunol Lett 72(2):69CrossRefPubMedGoogle Scholar
  5. Calderwood SK, Theriault JR, Gong J (2005) Message in a bottle: role of the 70-kDa heat shock protein family in anti-tumor immunity. Eur J Immunol 35(9):2518CrossRefPubMedGoogle Scholar
  6. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860CrossRefPubMedGoogle Scholar
  7. Derzsy Z, Prohaszka Z, Rigo J Jr, Fust G, Molvarec A (2010) Activation of the complement system in normal pregnancy and preeclampsia. Mol Immunol 47(7–8):1500CrossRefPubMedGoogle Scholar
  8. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan A (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105(6):685CrossRefPubMedGoogle Scholar
  9. Dybdahl B, Slordahl SA, Waage A, Kierulf P, Espevik T, Sundan A (2005) Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart 91(3):299CrossRefPubMedGoogle Scholar
  10. Eaden JA, Abrams KR, Mayberry JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48(4):526CrossRefPubMedGoogle Scholar
  11. Flohe SB, Bangen JM, Flohe S, Agrawal H, Bergmann K, Schade FU (2007) Origin of immunomodulation after soft tissue trauma: potential involvement of extracellular heat-shock proteins. Shock 27(5):494CrossRefPubMedGoogle Scholar
  12. Greene FL (2007) Current TNM staging of colorectal cancer. Lancet Oncol 8(7):572CrossRefPubMedGoogle Scholar
  13. Ishizuka M, Nagata H, Takagi K, Kubota K (2009) Influence of inflammation-based prognostic score on mortality of patients undergoing chemotherapy for far advanced or recurrent unresectable colorectal cancer. Ann Surg 250(2):268CrossRefPubMedGoogle Scholar
  14. Kocsis J, Madaras B, Toth EK, Fust G, Prohaszka Z (2010) Serum level of soluble 70-kD heat shock protein is associated with high mortality in patients with colorectal cancer without distant metastasis. Cell Stress Chaperones 15(2):143CrossRefPubMedGoogle Scholar
  15. Koike Y, Miki C, Okugawa Y, Yokoe T, Toiyama Y, Tanaka K, Inoue Y, Kusunoki M (2008) Preoperative C-reactive protein as a prognostic and therapeutic marker for colorectal cancer. J Surg Oncol 98(7):540CrossRefPubMedGoogle Scholar
  16. Kotler DP (2000) Cachexia. Ann Intern Med 133(8):622PubMedGoogle Scholar
  17. Molvarec A, Prohaszka Z, Nagy B, Szalay J, Fust G, Karadi I, Rigo J Jr (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case-control study. J Hum Hypertens 20(10):780CrossRefPubMedGoogle Scholar
  18. Molvarec A, Rigo J Jr, Lazar L, Balogh K, Mako V, Cervenak L, Mezes M, Prohaszka Z (2009) Increased serum heat-shock protein 70 levels reflect systemic inflammation, oxidative stress and hepatocellular injury in preeclampsia. Cell Stress Chaperones 14(2):151CrossRefPubMedGoogle Scholar
  19. Newcomb PA, Storer BE (1995) Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87(14):1067CrossRefPubMedGoogle Scholar
  20. Nozoe T, Matsumata T, Sugimachi K (2000) Preoperative elevation of serum C-reactive protein is related to impaired immunity in patients with colorectal cancer. Am J Clin Oncol 23(3):263PubMedGoogle Scholar
  21. Nozoe T, Mori E, Takahashi I, Ezaki T (2008) Preoperative elevation of serum C-reactive protein as an independent prognostic indicator of colorectal carcinoma. Surg Today 38(7):597CrossRefPubMedGoogle Scholar
  22. Pittet JF, Lee H, Morabito D, Howard MB, Welch WJ, Mackersie RC (2002) Serum levels of Hsp 72 measured early after trauma correlate with survival. J Trauma 52(4):611CrossRefPubMedGoogle Scholar
  23. Satoh M, Shimoda Y, Akatsu T, Ishikawa Y, Minami Y, Nakamura M (2006) Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte toll signal in patients with heart failure after acute myocardial infarction. Eur J Heart Fail 8(8):810CrossRefPubMedGoogle Scholar
  24. Szeplaki G, Varga L, Laki J, Dosa E, Rugonfalvi-Kiss S, Madsen HO, Prohaszka Z, Kocsis A, Gal P, Szabo A, Acsady G, Karadi I, Selmeci L, Garred P, Fust G, Entz L (2007) Low c1-inhibitor levels predict early restenosis after eversion carotid endarterectomy. Arterioscler Thromb Vasc Biol 27(12):2756CrossRefPubMedGoogle Scholar
  25. Varga L, Szeplaki G, Laki J, Kocsis A, Kristof K, Gal P, Bajtay Z, Wieslander J, Daha MR, Garred P, Madsen HO, Fust G, Farkas H (2008) Depressed activation of the lectin pathway of complement in hereditary angioedema. Clin Exp Immunol 153(1):68CrossRefPubMedGoogle Scholar
  26. Wang CS, Sun CF (2009) C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung Med J 32(5):471PubMedGoogle Scholar
  27. Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels 15(1):18CrossRefPubMedGoogle Scholar
  28. Ytting H, Christensen IJ, Jensenius JC, Thiel S, Nielsen HJ (2005) Preoperative mannan-binding lectin pathway and prognosis in colorectal cancer. Cancer Immunol Immunother 54(3):265CrossRefPubMedGoogle Scholar
  29. Ytting H, Christensen IJ, Thiel S, Jensenius JC, Nielsen HJ (2008) Pre- and postoperative levels in serum of mannan-binding lectin associated serine protease-2—a prognostic marker in colorectal cancer. Hum Immunol 69(7):414CrossRefPubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2010

Authors and Affiliations

  • Judit Kocsis
    • 1
  • Tamás Mészáros
    • 1
  • Balázs Madaras
    • 1
  • Éva Katalin Tóth
    • 1
  • Szilárd Kamondi
    • 2
  • Péter Gál
    • 2
  • Lilian Varga
    • 1
  • Zoltán Prohászka
    • 1
    • 3
  • George Füst
    • 1
  1. 1.Research Laboratory, 3rd Department of Internal MedicineSemmelweis UniversityBudapestHungary
  2. 2.Institute of EnzymologyHungarian Academy of SciencesBudapestHungary
  3. 3.Research Group of Inflammation and ImmunogeneticsHungarian Academy of SciencesBudapestHungary

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