Skip to main content
SpringerLink
Log in

Immunogenic Hsp-70 Is Overexpressed in Colorectal Cancers With High-Degree Microsatellite Instability

  • Original Contribution
  • Published:
Diseases of the Colon & Rectum

Abstract

PURPOSE

Colorectal cancers that display high-degree mi-crosatellite instability are associated with an improved prognosis and evidence of an activated host immune response. Molecular analyses have suggested that heat shock proteins, a family of proteins that have key immunologic functions, are upregulated in these cancers. We aimed to explore the expression of heat shock proteins 70 and 110 and their relationship to microsatellite instability, survival, and other clinicopathologic parameters.

METHODS

Twenty-six colorectal cancers that displayed microsatellite instability were matched by age, stage, and site in the colorectum to 26 microsatellite-stable cancers. Immunohistochemistry was used to detect expression of both markers.

RESULTS

The microsatellite-unstable group showed significantly higher expression of heat shock protein 70 than the microsatellite-stable group (P = 0.006), and patients undergoing curative resections for unstable cancers had improved prognosis compared with their stable counterparts (P = 0.026). Significantly, in a multivariate survival analysis, low or absent heat shock protein 70 expression was independently associated with a poor outcome (P = 0.001).

CONCLUSIONS

Heat shock protein 70 has known functions that promote antitumor immune responses. Its overexpression in colorectal cancers with microsatellite instability may be pivotal to explaining these tumors’ enhanced immunogenicity and improved prognosis.

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

Figure 1.
Figure 2.
Figure 3.

Similar content being viewed by others

REFERENCES

  1. AM Haydon JR Jass (2002) ArticleTitleEmerging pathways in colorectal-cancer development Lancet Oncol 3 83–8 Occurrence Handle11905459 Occurrence Handle10.1016/S1470-2045(02)00649-6 Occurrence Handle1:CAS:528:DC%2BD38XitFOjsLc%3D

    Article  PubMed  CAS  Google Scholar 

  2. RA Risques V Moreno M Ribas E Marcuello G Capella MA Peinado (2003) ArticleTitleGenetic pathways and genome-wide determinants of clinical outcome in colorectal cancer Cancer Res 63 7206–14 Occurrence Handle14612515 Occurrence Handle1:CAS:528:DC%2BD3sXovVGltrw%3D

    PubMed  CAS  Google Scholar 

  3. CR Boland SN Thibodeau SR Hamilton et al. (1998) ArticleTitleA National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer Cancer Res 58 5248–57 Occurrence Handle9823339 Occurrence Handle1:CAS:528:DyaK1cXnsFSmtbk%3D

    PubMed  CAS  Google Scholar 

  4. JM Cunningham ER Christensen DJ Tester et al. (1998) ArticleTitleHypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability Cancer Res 58 3455–60 Occurrence Handle9699680 Occurrence Handle1:CAS:528:DyaK1cXltFyis7Y%3D

    PubMed  CAS  Google Scholar 

  5. JG Herman A Umar K Polyak et al. (1998) ArticleTitleIncidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma Proc Natl Acad Sci USA 95 6870–5 Occurrence Handle9618505 Occurrence Handle10.1073/pnas.95.12.6870 Occurrence Handle1:CAS:528:DyaK1cXjslynu7s%3D

    Article  PubMed  CAS  Google Scholar 

  6. SN Thibodeau G Bren D Schaid (1993) ArticleTitleMicrosatellite instability in cancer of the proximal colon Science 260 816–9 Occurrence Handle8484122 Occurrence Handle10.1126/science.8484122 Occurrence Handle1:CAS:528:DyaK3sXkt1GlsLs%3D

    Article  PubMed  CAS  Google Scholar 

  7. R Gryfe H Kim ET Hsieh et al. (2000) ArticleTitleTumor microsatellite instability and clinical outcome in young patients with colorectal cancer N Engl J Med 342 69–77 Occurrence Handle10631274 Occurrence Handle10.1056/NEJM200001133420201 Occurrence Handle1:STN:280:DC%2BD3c%2FotVeitA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  8. RA Lothe P Peltomaki GI Meling et al. (1993) ArticleTitleGenomic instability in colorectal cancer: relationship to clinicopathological variables and family history Cancer Res 53 5849–52 Occurrence Handle8261392 Occurrence Handle1:CAS:528:DyaK2cXnsVCrsA%3D%3D

    PubMed  CAS  Google Scholar 

  9. S Popat R Hubner RS Houlston (2005) ArticleTitleSystematic review of microsatellite instability and colorectal cancer prognosis J Clin Oncol 23 609–18 Occurrence Handle15659508 Occurrence Handle10.1200/JCO.2005.01.086 Occurrence Handle1:CAS:528:DC%2BD2MXitVartLY%3D

    Article  PubMed  CAS  Google Scholar 

  10. H Elsaleh B Shannon B Iacopetta (2001) ArticleTitleMicrosatellite instability as a molecular marker for very good survival in colorectal cancer patients receiving adjuvant chemotherapy Gastroenterology 120 1309–10 Occurrence Handle11288748 Occurrence Handle1:STN:280:DC%2BD3M7pvFehtw%3D%3D Occurrence Handle10.1053/gast.2001.23646

    Article  PubMed  CAS  Google Scholar 

  11. C Ribic DJ Sargent MJ Moore et al. (2003) ArticleTitleTumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer N Engl J Med 349 247–57 Occurrence Handle12867608 Occurrence Handle10.1056/NEJMoa022289 Occurrence Handle1:CAS:528:DC%2BD3sXlsVGjsbY%3D

    Article  PubMed  CAS  Google Scholar 

  12. JM Carethers EJ Smith CA Behling et al. (2004) ArticleTitleUse of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer Gastroenterology 126 394–401 Occurrence Handle14762775 Occurrence Handle10.1053/j.gastro.2003.12.023 Occurrence Handle1:CAS:528:DC%2BD2cXhvV2rsbo%3D

    Article  PubMed  CAS  Google Scholar 

  13. JR Jass KA Do LA Simms et al. (1998) ArticleTitleMorphology of sporadic colorectal cancer with DNA replication errors Gut 42 673–9 Occurrence Handle9659163 Occurrence Handle1:STN:280:DyaK1czitlaquw%3D%3D Occurrence Handle10.1136/gut.42.5.673

    Article  PubMed  CAS  Google Scholar 

  14. R Dolcetti A Viel C Doglioni et al. (1999) ArticleTitleHigh prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability Am J Pathol 154 1805–13 Occurrence Handle10362805 Occurrence Handle1:STN:280:DyaK1M3ptlShtA%3D%3D

    PubMed  CAS  Google Scholar 

  15. M Guidoboni R Gafa A Viel et al. (2001) ArticleTitleMicrosatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis Am J Pathol 159 297–304 Occurrence Handle11438476 Occurrence Handle1:STN:280:DC%2BD3Mzpt1arsQ%3D%3D

    PubMed  CAS  Google Scholar 

  16. SM Phillips A Banerjea R Feakins SR Li SA Bustin S Dorudi (2004) ArticleTitleTumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic Br J Surg 91 469–75 Occurrence Handle15048750 Occurrence Handle10.1002/bjs.4472 Occurrence Handle1:STN:280:DC%2BD2c7lsVWnsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  17. A Banerjea S Ahmed R Hands et al. (2004) ArticleTitleColorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity Mol Cancer 3 21 Occurrence Handle15298707 Occurrence Handle10.1186/1476-4598-3-21 Occurrence Handle1:CAS:528:DC%2BD2MXktVCht7o%3D

    Article  PubMed  CAS  Google Scholar 

  18. W Bodmer T Bishop P Karran (1994) ArticleTitleGenetic steps in colorectal cancer Nat Genet 6 217–9 Occurrence Handle8012377 Occurrence Handle10.1038/ng0394-217 Occurrence Handle1:STN:280:DyaK2c3ot1SlsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  19. I Saeterdal MK Gjertsen P Straten JA Eriksen G Gaudernack (2001) ArticleTitleA TGF betaRII frameshift-mutation-derived CTL epitope recognised by HLA-A2-restricted CD8+ T cells Cancer Immunol Immunother 50 469–76 Occurrence Handle11761441 Occurrence Handle10.1007/s002620100222 Occurrence Handle1:CAS:528:DC%2BD38Xjsl2jtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  20. I Saeterdal J Bjorheim K Lislerud et al. (2001) ArticleTitleFrameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer Proc Natl Acad Sci USA 98 13255–60 Occurrence Handle11687624 Occurrence Handle10.1073/pnas.231326898 Occurrence Handle1:CAS:528:DC%2BD3MXosFygt70%3D

    Article  PubMed  CAS  Google Scholar 

  21. C Castelli L Rivoltini F Rini et al. (2004) ArticleTitleHeat shock proteins: biological functions and clinical application as personalized vaccines for human cancer Cancer Immunol Immunother 53 227–33 Occurrence Handle14689240 Occurrence Handle10.1007/s00262-003-0481-9 Occurrence Handle1:CAS:528:DC%2BD2cXhtlehsLc%3D

    Article  PubMed  CAS  Google Scholar 

  22. A Banerjea SM Phillips S Dorudi SA Bustin (2003) ArticleTitleColorectal cancers with mononucleotide microsatellite instability can be identified using microfabricated chip technology Anal Biochem 322 130–3 Occurrence Handle14705790 Occurrence Handle10.1016/j.ab.2003.07.006 Occurrence Handle1:CAS:528:DC%2BD3sXns1Kktb4%3D

    Article  PubMed  CAS  Google Scholar 

  23. AC Lazaris GE Theodoropoulos PS Davaris et al. (1995) ArticleTitleHeat shock protein 70 and HLA-DR molecules tissue expression. Prognostic implications in colorectal cancer Dis Colon Rectum 38 739–45 Occurrence Handle7607036 Occurrence Handle10.1007/BF02048033 Occurrence Handle1:STN:280:DyaK2MzjtFSrtw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  24. DG Altman JM Bland (1983) ArticleTitleMeasurement in medicine—the analysis of method comparison studies Statistician 32 307–17 Occurrence Handle10.2307/2987937

    Article  Google Scholar 

  25. SM Todryk AA Melcher AG Dalgleish RG Vile (2000) ArticleTitleHeat shock proteins refine the danger theory Immunology 99 334–7 Occurrence Handle10712661 Occurrence Handle10.1046/j.1365-2567.2000.00002.x Occurrence Handle1:CAS:528:DC%2BD3cXitVent74%3D

    Article  PubMed  CAS  Google Scholar 

  26. AG Pockley (2003) ArticleTitleHeat shock proteins as regulators of the immune response Lancet 362 469–76 Occurrence Handle12927437 Occurrence Handle10.1016/S0140-6736(03)14075-5 Occurrence Handle1:CAS:528:DC%2BD3sXmt1ajsrk%3D

    Article  PubMed  CAS  Google Scholar 

  27. SM Todryk AA Melcher N Hardwick et al. (1999) ArticleTitleHeat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake J Immunol 163 1398–408 Occurrence Handle10415040 Occurrence Handle1:CAS:528:DyaK1MXkslOgsrY%3D

    PubMed  CAS  Google Scholar 

  28. J Banchereau RM Steinman (1998) ArticleTitleDendritic cells and the control of immunity Nature 392 245–52 Occurrence Handle9521319 Occurrence Handle10.1038/32588 Occurrence Handle1:CAS:528:DyaK1cXitFWrsr8%3D

    Article  PubMed  CAS  Google Scholar 

  29. DC Bicknell L Kaklamanis R Hampson WF Bodmer P Karran (1996) ArticleTitleSelection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas Curr Biol 6 1695–7 Occurrence Handle8994836 Occurrence Handle10.1016/S0960-9822(02)70795-1 Occurrence Handle1:STN:280:DyaK2s7kvVajtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  30. E Noessner R Gastpar V Milani et al. (2002) ArticleTitleTumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells J Immunol 169 5424–32 Occurrence Handle12421917 Occurrence Handle1:CAS:528:DC%2BD38Xoslyqtb4%3D

    PubMed  CAS  Google Scholar 

  31. F Belli A Testori L Rivoltini et al. (2002) ArticleTitleVaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings J Clin Oncol 20 4169–80 Occurrence Handle12377960 Occurrence Handle10.1200/JCO.2002.09.134 Occurrence Handle1:CAS:528:DC%2BD38XnsFyqsbg%3D

    Article  PubMed  CAS  Google Scholar 

  32. V Mazzaferro J Coppa MG Carrabba et al. (2003) ArticleTitleVaccination with autologous tumor-derived heat-shock protein Gp96 after liver resection for metastatic colorectal cancer Clin Cancer Res 9 3235–45 Occurrence Handle12960108 Occurrence Handle1:CAS:528:DC%2BD3sXotFCksL4%3D

    PubMed  CAS  Google Scholar 

  33. L Rivoltini C Castelli M Carrabba et al. (2003) ArticleTitleHuman tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells J Immunol 171 3467–74 Occurrence Handle14500642 Occurrence Handle1:CAS:528:DC%2BD3sXnvFSrt74%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Academic Surgery, Barts and the London Queen Mary School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London, United Kingdom

    Ayan Banerjea M.D., Simon M. Phillips M.D., Michael P. Powar M.D., Stephen A. Bustin Ph.D. & Sina Dorudi Ph.D.

  2. Department of Histopathology, The Royal London Hospital, Whitechapel, London, United Kingdom

    Roger M. Feakins M.D.

  3. ICMS Pathology, Institute of Pathology, The Royal London Hospital, Whitechapel, London, United Kingdom

    Carole D. Nickols M.Phil.

Authors
  1. Ayan Banerjea M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger M. Feakins M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carole D. Nickols M.Phil.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon M. Phillips M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael P. Powar M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen A. Bustin Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sina Dorudi Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayan Banerjea M.D..

Additional information

Supported by the Bowel & Cancer Research, Registered U.K. Charity No. 328667.

About this article

Cite this article

Banerjea, A., Feakins, R., Nickols, C. et al. Immunogenic Hsp-70 Is Overexpressed in Colorectal Cancers With High-Degree Microsatellite Instability. Dis Colon Rectum 48, 2322–2328 (2005). https://doi.org/10.1007/s10350-005-0203-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-005-0203-9

Key words

Search

Navigation