Abstract
Many findings indicate that measuring the serum concentration of soluble 70-kD heat shock protein (soluble HSP70) may provide important information in cardiovascular, inflammatory, and pregnancy-related diseases; however, only scarce data are available in cancer. Therefore, using a commercial ELISA kit, we measured soluble HSP70 concentration in the sera of 179 patients with colorectal cancer. We investigated the relationship between soluble HSP70 concentration and mortality, during 33.0 (24.4–44.0) months long follow-up. High (>1.65 pg/ml, median concentration) soluble HSP70 level was a significant (hazard ratio: 1.88 (1.20–2.96, p = 0.005) predictor of mortality during the follow-up period. When we compared the soluble HSP70 levels in patients with non-resected primary tumors as compared to those who were recruited into the study 4–6 weeks after the tumor resection they were found to be significantly (p = 0.020) higher in the former group. Since the patients with non-resected primary tumors had also distant metastasis and died early, we limited the further analysis to 142 patients with no distant metastasis at the beginning of the follow-up. This association remained significant even after multiple Cox-regression analysis had been performed to adjust the data for age and sex (p = 0.028); age, sex, and TNM-T stage (p = 0.041); age, sex, and TNM-N stage (p = 0.021); age, sex, and histological grade (p = 0.023); or age, sex, and tumor localization (p = 0.029). Further analysis showed that the significant association between high HSP70 levels and poor survival is in the strongest in the group of <70-year-old female patients (HR: 5.52 (2.02-15.15), p = 0.001), as well as in those who were in a less advanced stage of the disease at baseline. These novel findings indicate that the serum level of soluble HSP70 might prove a useful, stage-independent prognostic marker in colorectal cancer without distant metastasis.
Similar content being viewed by others
References
Abe M, Manola JB, Oh WK, Parslow DL, George DJ, Austin CL, Kantoff PW (2004) Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer. Clin Prostate Cancer 3(1):49
Broquet AH, Thomas G, Masliah J, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278(24):21601
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):2518
Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31(3):164
Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10(2):86
Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M, Neoptolemos JP, Ke Y, Foster CS (2000) Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60(24):7099
Dundas SR, Lawrie LC, Rooney PH, Murray GI (2005) Mortalin is over-expressed by colorectal adenocarcinomas and correlates with poor survival. J Pathol 205(1):74
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):685
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):299
Elpek GO, Karaveli S, Simsek T, Keles N, Aksoy NH (2003) Expression of heat-shock proteins hsp27, hsp70 and hsp90 in malignant epithelial tumour of the ovaries. Apmis 111(4):523
Farkas B, Hantschel M, Magyarlaki M, Becker B, Scherer K, Landthaler M, Pfister K, Gehrmann M, Gross C, Mackensen A, Multhoff G (2003) Heat shock protein 70 membrane expression and melanoma-associated marker phenotype in primary and metastatic melanoma. Melanoma Res 13(2):147
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):494
Gehrmann M, Schmetzer H, Eissner G, Haferlach T, Hiddemann W, Multhoff G (2003) Membrane-bound heat shock protein 70 (Hsp70) in acute myeloid leukemia: a tumor specific recognition structure for the cytolytic activity of autologous NK cells. Haematologica 88(4):474
Greene FL (2007) Current TNM staging of colorectal cancer. Lancet Oncol 8(7):572
Grodstein F, Newcomb PA, Stampfer MJ (1999) Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106(5):574
Hwang TS, Han HS, Choi HK, Lee YJ, Kim YJ, Han MY, Park YM (2003) Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancer. J Gastroenterol Hepatol 18(6):690
Kaur J, Ralhan R (1995) Differential expression of 70-kDa heat shock-protein in human oral tumorigenesis. Int J Cancer 63(6):774
Lazaris A, Chatzigianni EB, Panoussopoulos D, Tzimas GN, Davaris PS, Golematis B (1997) Proliferating cell nuclear antigen and heat shock protein 70 immunolocalization in invasive ductal breast cancer not otherwise specified. Breast Cancer Res Treat 43(1):43
Madach K, Molvarec A, Rigo J Jr, Nagy B, Penzes I, Karadi I, Prohaszka Z (2008) Elevated serum 70 kDa heat shock protein level reflects tissue damage and disease severity in the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Eur J Obstet Gynecol Reprod Biol 139(2):133
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):780
Molvarec A, Rigo J Jr, Nagy B, Walentin S, Szalay J, Fust G, Karadi I, Prohaszka Z (2007) Serum heat shock protein 70 levels are decreased in normal human pregnancy. J Reprod Immunol 74(1-2):163
Molvarec A, Derzsy Z, Kocsis J, Boze T, Nagy B, Balogh K, Mako V, Cervenak L, Mezes M, Karadi I, Prohaszka Z, Rigo J Jr (2009) Circulating anti-heat-shock-protein antibodies in normal pregnancy and preeclampsia. Cell Stress Chaperones in press
Multhoff G, Botzler C, Wiesnet M, Muller E, Meier T, Wilmanns W, Issels RD (1995) A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer 61(2):272
Multhoff G, Pfister K, Botzler C, Jordan A, Scholz R, Schmetzer H, Burgstahler R, Hiddemann W (2000) Adoptive transfer of human natural killer cells in mice with severe combined immunodeficiency inhibits growth of Hsp70-expressing tumors. Int J Cancer 88(5):791
Newcomb PA, Storer BE (1995) Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87(14):1067
Newcomb PA, Zheng Y, Chia VM, Morimoto LM, Doria-Rose VP, Templeton A, Thibodeau SN, Potter JD (2007) Estrogen plus progestin use, microsatellite instability, and the risk of colorectal cancer in women. Cancer Res 67(15):7534
Nickerson M, Kennedy SL, Johnson JD, Fleshner M (2006) Sexual dimorphism of the intracellular heat shock protein 72 response. J Appl Physiol 101(2):566
Njemini R, Lambert M, Demanet C, Mets T (2003) Elevated serum heat-shock protein 70 levels in patients with acute infection: use of an optimized enzyme-linked immunosorbent assay. Scand J Immunol 58(6):664
Ogata Y, Murakami H, Sasatomi T, Ishibashi N, Mori S, Ushijima M, Akagi Y, Shirouzu K (2009) Elevated preoperative serum carcinoembrionic antigen level may be an effective indicator for needing adjuvant chemotherapy after potentially curative resection of stage II colon cancer. J Surg Oncol 99(1):65
Park CS, Joo IS, Song SY, Kim DS, Bae DS, Lee JH (1999) An immunohistochemical analysis of heat shock protein 70, p53, and estrogen receptor status in carcinoma of the uterine cervix. Gynecol Oncol 74(1):53
Pfister K, Radons J, Busch R, Tidball JG, Pfeifer M, Freitag L, Feldmann HJ, Milani V, Issels R, Multhoff G (2007) Patient survival by Hsp70 membrane phenotype: association with different routes of metastasis. Cancer 110(4):926
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):611
Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27(6):367
Pockley AG, Bulmer J, Hanks BM, Wright BH (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4(1):29
Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegard J (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens 20(9):1815
Pockley AG, Georgiades A, Thulin T, de Faire U, Frostegard J (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42(3):235
Rau B, Gaestel M, Wust P, Stahl J, Mansmann U, Schlag PM, Benndorf R (1999) Preoperative treatment of rectal cancer with radiation, chemotherapy and hyperthermia: analysis of treatment efficacy and heat-shock response. Radiat Res 151(4):479
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama 288(3):321
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)):810
Suzuki K, Ito Y, Wakai K, Kawado M, Hashimoto S, Seki N, Ando M, Nishino Y, Kondo T, Watanabe Y, Ozasa K, Inoue T, Tamakoshi A (2006) Serum heat shock protein 70 levels and lung cancer risk: a case-control study nested in a large cohort study. Cancer Epidemiol Biomarkers Prev 15(9):1733
Takagawa R, Fujii S, Ohta M, Nagano Y, Kunisaki C, Yamagishi S, Osada S, Ichikawa Y, Shimada H (2008) Preoperative serum carcinoembryonic antigen level as a predictive factor of recurrence after curative resection of colorectal cancer. Ann Surg Oncol 15(12):3433
Takahashi S, Mikami T, Watanabe Y, Okazaki M, Okazaki Y, Okazaki A, Sato T, Asaishi K, Hirata K, Narimatsu E et al (1994) Correlation of heat shock protein 70 expression with estrogen receptor levels in invasive human breast cancer. Am J Clin Pathol 101(4):519
Terry DF, Wyszynski DF, Nolan VG, Atzmon G, Schoenhofen EA, Pennington JY, Andersen SL, Wilcox MA, Farrer LA, Barzilai N, Baldwin CT, Asea A (2006) Serum heat shock protein 70 level as a biomarker of exceptional longevity. Mech Ageing Dev 127(11):862
Vargas-Roig LM, Fanelli MA, Lopez LA, Gago FE, Tello O, Aznar JC, Ciocca DR (1997) Heat shock proteins and cell proliferation in human breast cancer biopsy samples. Cancer Detect Prev 21(5):441
Voss MR, Stallone JN, Li M, Cornelussen RN, Knuefermann P, Knowlton AA (2003) Gender differences in the expression of heat shock proteins: the effect of estrogen. Am J Physiol Heart Circ Physiol 285(2):H687
Wang WS, Lin JK, Chiou TJ, Liu JH, Fan FS, Yen CC, Lin TC, Jiang JK, Yang SH, Wang HS, Chen PM (2002) CA19-9 as the most significant prognostic indicator of metastatic colorectal cancer. Hepatogastroenterology 49(43):160
Wang JY, Lu CY, Chu KS, Ma CJ, Wu DC, Tsai HL, Yu FJ, Hsieh JS (2007) Prognostic significance of pre- and postoperative serum carcinoembryonic antigen levels in patients with colorectal cancer. Eur Surg Res 39(4):245
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):8
Zhong L, Peng X, Hidalgo GE, Doherty DE, Stromberg AJ, Hirschowitz EA (2003) Antibodies to HSP70 and HSP90 in serum in non-small cell lung cancer patients. Cancer Detect Prev 27(4):285
Zhu J, Quyyumi AA, Wu H, Csako G, Rott D, Zalles-Ganley A, Ogunmakinwa J, Halcox J, Epstein SE (2003) Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol 23(6):1055
Acknowledgments
This work was supported by the OTKA T049266 grant (GF) and NF72689 grant (ZP) of the Hungarian Research Fund.
Author information
Authors and Affiliations
Corresponding author
Additional information
Judit Kocsis and Balázs Madaras equally contributed to the work; therefore, they share the first authorship.
Rights and permissions
About this article
Cite this article
Kocsis, J., Madaras, B., Tóth, É.K. et al. Serum level of soluble 70-kD heat shock protein is associated with high mortality in patients with colorectal cancer without distant metastasis. Cell Stress and Chaperones 15, 143–151 (2010). https://doi.org/10.1007/s12192-009-0128-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-009-0128-7