Pathology & Oncology Research

, Volume 23, Issue 2, pp 377–383 | Cite as

Serum Heat Shock Protein 70, as a Potential Biomarker for Small Cell Lung Cancer

  • Madaras Balázs
  • Horváth Zsolt
  • Gráf László
  • Gálffy Gabriella
  • Tamási Lilla
  • Ostoros Gyula
  • Döme Balázs
  • Mórocz Éva
  • Bártfai Zoltán
  • Prohászka Zoltán
  • Kocsis JuditEmail author
Original Article


The 70 kDa heat shock protein (Hsp70) is a highly conservative molecular chaperone, that has important role in cell integrity. Recently considerable amount of data are accumulating on the potential role of Hsp70 in carcinogenesis and tumor progression. Most papers are focusing on intracellular or membrane bound protein, however very limited data exist on serum Hsp70, that can also induce innate and adaptive immune response. Previously we have published data on the correlation between coloretal cancer progression and serum Hsp70 concentration. The objective of this study was to compare the serum Hsp70 level in patients with small cell lung cancer (SCLC n = 70) and age matched healthy controlls (n = 121) and correlate Hsp70 level with other known serum biomarkers (LDH and NSE) of the disease. We found that the serum level of Hsp70 was significantly higher in SCLC patients compared to control subjects (mean value 6.91 vs 2.47 ng/ml, p = 0.001). The highest Hsp70 concentration was measured in stage IV advanced SCLC (Stage IV versus Stage I-III disease: 9.91 vs 4.38 ng/ml, p = 0.003). The serum Hsp70 level correlated with serum LDH (r = 0.426, p < 0,001) and NSE level (r = 0.455, p < 0,001). We found that high serum Hsp70 level predicted unfavorable survival, risk of death within 1 year was more than 3 times higher in patients with high baseline Hsp70 level (HR:3.509, CI: 1.066–11.562; p = 0.039). Our observations indicate that serum Hsp70 could be a valuable diagnostic and prognostic marker in small cell lung cancer.


Small cell lung cancer Hsp70 Biomarker Prognostic marker Target 


  1. 1.
    Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL (1998) Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 8(6):657–665CrossRefPubMedGoogle Scholar
  2. 2.
    Rerole AL, Jego G, Garrido C (2011) Hsp70: anti-apoptotic and tumorigenic protein. Methods Mol Biol 787:205–230. doi: 10.1007/978-1-61779-295-3_16 CrossRefPubMedGoogle Scholar
  3. 3.
    Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jaattela M (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A 97(14):7871–7876CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nature reviews. Immunology 2(3):185–194. doi: 10.1038/nri749 PubMedGoogle Scholar
  5. 5.
    Nicchitta CV (2003) Re-evaluating the role of heat-shock protein-peptide interactions in tumour immunity. Nature reviews. Immunology 3(5):427–432. doi: 10.1038/nri1089 PubMedGoogle Scholar
  6. 6.
    Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23(16):2907–2918. doi: 10.1038/sj.onc.1207529 CrossRefPubMedGoogle Scholar
  7. 7.
    Whitesell L, Lindquist S (2009) Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin Ther Targets 13(4):469–478. doi: 10.1517/14728220902832697 CrossRefPubMedGoogle Scholar
  8. 8.
    Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581(19):3758–3769. doi: 10.1016/j.febslet.2007.05.040 CrossRefPubMedGoogle Scholar
  9. 9.
    Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31(3):164–172. doi: 10.1016/j.tibs.2006.01.006 CrossRefPubMedGoogle Scholar
  10. 10.
    Buzzard KA, Giaccia AJ, Killender M, Anderson RL (1998) Heat shock protein 72 modulates pathways of stress-induced apoptosis. J Biol Chem 273(27):17147–17153CrossRefPubMedGoogle Scholar
  11. 11.
    Garrido CGS, Ravagnan L, Kroemer G (2001) Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun 286(3):433–442CrossRefPubMedGoogle Scholar
  12. 12.
    Ciocca DR, Arrigo AP, Calderwood SK (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87(1):19–48. doi: 10.1007/s00204-012-0918-z CrossRefPubMedGoogle Scholar
  13. 13.
    Ciocca DR, Clark GM, Tandon AK, Fuqua SA, Welch WJ, McGuire WL (1993) Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications. J Natl Cancer Inst 85(7):570–574CrossRefPubMedGoogle Scholar
  14. 14.
    Thanner F, Sütterlin MW, Kapp M, Rieger L, Kristen P, Dietl J, Gassel AM, Müller T (2003) Heat-shock protein 70 as a prognostic marker in node-negative breast cancer. Anticancer Res 23(2 A):1057–1062PubMedGoogle Scholar
  15. 15.
    Liu FF, Miller N, Levin W, Zanke B, Cooper B, Henry M, Sherar MD, Pintilie M, Hunt JW, Hill RP (1996) The potential role of HSP70 as an indicator of response to radiation and hyperthermia treatments for recurrent breast cancer. Int J Hyperth 12(2):197–208 discussion 209–110CrossRefGoogle Scholar
  16. 16.
    Vargas-Roig LM, Gago FE, Tello O, Aznar JC, Ciocca DR (1998) Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer 79(5):468–475CrossRefPubMedGoogle Scholar
  17. 17.
    Nanbu K, Konishi I, Mandai M, Kuroda H, Hamid AA, Komatsu T, Mori T (1998) Prognostic significance of heat shock proteins HSP70 and HSP90 in endometrial carcinomas. Cancer Detect Prev 22(6):549–555CrossRefPubMedGoogle Scholar
  18. 18.
    Piura B, Rabinovich A, Yavelsky V, Wolfson M (2002) Heat shock proteins and malignancies of the female genital tract. Harefuah 141(11):969–972PubMedGoogle Scholar
  19. 19.
    Syrigos KN, Harrington KJ, Karayiannakis AJ, Sekara E, Chatziyianni E, Syrigou EI, Waxman J (2003) Clinical significance of heat shock protein-70 expression in bladder cancer. Urology 61(3):677–680CrossRefPubMedGoogle Scholar
  20. 20.
    Kumar S, Stokes J, 3rd, Singh UP, Scissum Gunn K, Acharya A, Manne U, Mishra M (2016) Targeting Hsp70: a possible therapy for cancer. Cancer Lett 374(1):156–166. doi: 10.1016/j.canlet.2016.01.056
  21. 21.
    Multhoff G, Pockley AG, Schmid TE, Schilling D (2015) The role of heat shock protein 70 (Hsp70) in radiation-induced immunomodulation. Cancer Lett 368(2):179–184. doi: 10.1016/j.canlet.2015.02.013 CrossRefPubMedGoogle Scholar
  22. 22.
    Specht HM, Ahrens N, Blankenstein C, Duell T, Fietkau R, Gaipl US, Gunther C, Gunther S, Habl G, Hautmann H, Hautmann M, Huber RM, Molls M, Offner R, Rodel C, Rodel F, Schutz M, Combs SE, Multhoff G (2015) Heat shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) - From Preclinical Studies to a Clinical Phase II Trial. Front Immunol 6:162. doi: 10.3389/fimmu.2015.00162 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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):143–151. doi: 10.1007/s12192-009-0128-7 CrossRefPubMedGoogle Scholar
  24. 24.
    Yeh CH, Tseng R, Zhang Z, Cortes J, O'Brien S, Giles F, Hannah A, Estrov Z, Keating M, Kantarjian H, Albitar M (2009) Circulating heat shock protein 70 and progression in patients with chronic myeloid leukemia. Leuk Res 33(2):212–217. doi: 10.1016/j.leukres.2008.07.012 CrossRefPubMedGoogle Scholar
  25. 25.
    Gehrmann M, Specht HM, Bayer C, Brandstetter M, Chizzali B, Duma M, Breuninger S, Hube K, Lehnerer S, van Phi V, Sage E, Schmid TE, Sedelmayr M, Schilling D, Sievert W, Stangl S, Multhoff G (2014) Hsp70--a biomarker for tumor detection and monitoring of outcome of radiation therapy in patients with squamous cell carcinoma of the head and neck. Radiat Oncol 9:131. doi: 10.1186/1748-717X-9-131 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kocsis J, Meszaros T, Madaras B, Toth EK, Kamondi S, Gal P, Varga L, Prohaszka Z, Fust G (2011) High levels of acute phase proteins and soluble 70 kDa heat shock proteins are independent and additive risk factors for mortality in colorectal cancer. Cell Stress Chaperones 16(1):49–55. doi: 10.1007/s12192-010-0220-z CrossRefPubMedGoogle Scholar
  27. 27.
    Dutta SK, Girotra M, Singla M, Dutta A, Otis Stephen F, Nair PP, Merchant NB (2012) Serum HSP70: a novel biomarker for early detection of pancreatic cancer. Pancreas 41(4):530–534. doi: 10.1097/MPA.0b013e3182374ace CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sato Y, Harada K, Sasaki M, Yasaka T, Nakanuma Y (2012) Heat shock proteins 27 and 70 are potential biliary markers for the detection of cholangiocarcinoma. Am J Pathol 180(1):123–130. doi: 10.1016/j.ajpath.2011.09.010 CrossRefPubMedGoogle Scholar
  29. 29.
    Zimmermann M, Nickl S, Lambers C, Hacker S, Mitterbauer A, Hoetzenecker K, Rozsas A, Ostoros G, Laszlo V, Hofbauer H, Renyi-Vamos F, Klepetko W, Dome B, Ankersmit HJ (2012) Discrimination of clinical stages in non-small cell lung cancer patients by serum HSP27 and HSP70: a multi-institutional case-control study. Clinica Chimica Acta; Int J Clin Chem 413(13–14):1115–1120. doi: 10.1016/j.cca.2012.03.008 CrossRefGoogle Scholar
  30. 30.
    Qiao Y, Liu B, Li Z (2008) Activation of NK cells by extracellular heat shock protein 70 through induction of NKG2D ligands on dendritic cells. Cancer Immun 8:12PubMedPubMedCentralGoogle Scholar
  31. 31.
    Varano Della Vergiliana JF, Lansley SM, Porcel JM, Bielsa S, Brown JS, Creaney J, Temple SE, Waterer GW, Lee YC (2013) Bacterial infection elicits heat shock protein 72 release from pleural mesothelial cells. PLoS One 8(5):e63873. doi: 10.1371/journal.pone.0063873 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Brueckl WM, Herbst L, Lechler A, Fuchs F, Schoeberl A, Zirlik S, Klein P, Brunner TB, Papadopoulos T, Hohenberger W, Hahn EG, Wiest GH (2006) Predictive and prognostic factors in small cell lung carcinoma (SCLC)--analysis from routine clinical practice. Anticancer Res 26(6C):4825–4832PubMedGoogle Scholar
  33. 33.
    Byhardt RW, Hartz A, Libnoch JA, Hansen R, Cox JD (1986) Prognostic influence of TNM staging and LDH levels in small cell carcinoma of the lung (SCCL. Int J Radiat Oncol Biol Phys 12(5):771–777CrossRefPubMedGoogle Scholar
  34. 34.
    Sagman U, Feld R, Evans WK, Warr D, Shepherd FA, Payne D, Pringle J, Yeoh J, DeBoer G, Malkin A (1991) The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer. J Clin Oncol 9(6):954–961CrossRefPubMedGoogle Scholar
  35. 35.
    Ganz PA, Ma PY, Wang HJ, Elashoff RM (1987) Evaluation of three biochemical markers for serially monitoring the therapy of small-cell lung cancer. J Clin Oncol 5(3):472–479CrossRefPubMedGoogle Scholar
  36. 36.
    Bremnes RM, Sundstrom S, Aasebø U, Kaasa S, Hatlevoll R, Aamdal S, Group NLCS (2003) The value of prognostic factors in small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow-up. Lung Cancer 39(3):303–313CrossRefPubMedGoogle Scholar
  37. 37.
    Ando S, Suzuki M, Yamamoto N, Iida T, Kimura H (2004) The prognostic value of both neuron-specific enolase (NSE) and Cyfra21-1 in small cell lung cancer. Anticancer Res 24(3b):1941–1946PubMedGoogle Scholar
  38. 38.
    Molina R, Auge JM, Filella X, Vinolas N, Alicarte J, Domingo JM, Ballesta AM (2005) Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer. Anticancer Res 25(3 A):1773–1778PubMedGoogle Scholar
  39. 39.
    Kocsis J, Mészáros T, Madaras B, Tóth EK, Kamondi S, Gál P, Varga L, Prohászka Z, Füst G (2011) High levels of acute phase proteins and soluble 70 kDa heat shock proteins are independent and additive risk factors for mortality in colorectal cancer. Cell Stress Chaperones 16(1):49–55. doi: 10.1007/s12192-010-0220-z CrossRefPubMedGoogle Scholar
  40. 40.
    Rozenberg P, Kocsis J, Saar M, Prohaszka Z, Fust G, Fishelson Z (2013) Elevated levels of mitochondrial mortalin and cytosolic HSP70 in blood as risk factors in patients with colorectal cancer. Int J Cancer J Int du Cancer 133(2):514–518. doi: 10.1002/ijc.28029 CrossRefGoogle Scholar
  41. 41.
    Calderwood SK, Ciocca DR (2008) Heat shock proteins: stress proteins with Janus-like properties in cancer. Int J Hyperth 24(1):31–39. doi: 10.1080/02656730701858305 CrossRefGoogle Scholar
  42. 42.
    Sherman M, Multhoff G (2007) Heat shock proteins in cancer. Ann N Y Acad Sci 1113:192–201. doi: 10.1196/annals.1391.030 CrossRefPubMedGoogle Scholar
  43. 43.
    Radons J, Multhoff G (2005) Immunostimulatory functions of membrane-bound and exported heat shock protein 70. Exerc Immunol Rev 11:17–33PubMedGoogle Scholar
  44. 44.
    Multhoff G, Mizzen L, Winchester CC, Milner CM, Wenk S, Eissner G, Kampinga HH, Laumbacher B, Johnson J (1999) Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 27(11):1627–1636CrossRefPubMedGoogle Scholar
  45. 45.
    Jagadish N, Parashar D, Gupta N, Agarwal S, Suri V, Kumar R, Suri V, Sadasukhi TC, Gupta A, Ansari AS, Lohiya NK, Suri A (2016) Heat shock protein 70–2 (HSP70–2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth. BMC Cancer 16(1):561. doi: 10.1186/s12885-016-2592-7 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wen W, Liu W, Shao Y, Chen L (2014) VER-155008, a small molecule inhibitor of HSP70 with potent anti-cancer activity on lung cancer cell lines. Exp Biol Med (Maywood) 239(5):638–645. doi: 10.1177/1535370214527899 CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2016

Authors and Affiliations

  • Madaras Balázs
    • 1
  • Horváth Zsolt
    • 2
  • Gráf László
    • 3
  • Gálffy Gabriella
    • 4
  • Tamási Lilla
    • 4
  • Ostoros Gyula
    • 5
  • Döme Balázs
    • 5
  • Mórocz Éva
    • 6
  • Bártfai Zoltán
    • 7
  • Prohászka Zoltán
    • 3
  • Kocsis Judit
    • 2
    • 3
    Email author
  1. 1.National Institute of OncologyBudapestHungary
  2. 2.Institute of OncologyUniversity of DebrecenDebrecenHungary
  3. 3.3rd Department of Internal MedicineSemmelweis University BudapestBudapestHungary
  4. 4.Department of PulmonologySemmelweis University BudapestBudapestHungary
  5. 5.Department of Tumor BiologyNational Koranyi Institute of PulmonologyBudapestHungary
  6. 6.Pulmonology HospitalTörökbálintHungary
  7. 7.Department of PulmonologyElizabeth Teaching Hospital and Rehabilitation Institute SopronSopronHungary

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