Skip to main content
SpringerLink
Log in

Desmoplastic Reaction Influences Pancreatic Cancer Growth Behavior

  • Original Scientific Reports
  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Connective tissue growth factor (CTGF), which is regulated by transforming growth factor-ß (TGFß), has recently been implicated in the pathogenesis of fibrotic diseases and tumor stroma. Inasmuch as generation of desmoplastic tissue is characteristic for pancreatic cancer, it is not known whether it gives pancreatic cancer cells a growth advantage or is a reaction of the body to inhibit cancer cell progression. In the present study we analyzed the expression and localization of CTGF and evaluated whether it influences the prognosis of pancreas cancer. Tissue samples were obtained from 25 individuals (6 women, 19 men) undergoing pancreatic resection for pancreatic cancer. Tissue samples from 13 previously healthy organ donors (5 women, 8 men) served as controls. Expression of CTGF was studied by Northern blot analysis. In situ hybridization and immunohistochemistry localized the respective mRNA moieties and proteins in the tissue samples. Northern blot analysis revealed that pancreatic cancer tissue samples exhibited a 46-fold increase in CTGF mRNA expression (p < 0.001) over that of normal controls. In vitro studies confirmed that pancreatic stellate cells are the major source of CTGF mRNA expression and revealed a large variance in basal and TGFß-induced CTGF expression in cultured pancreatic cancer cells. This could also be confirmed by in situ hybridization, indicating that CTGF mRNA signals were located principally in fibroblasts, with only weak signals in the cancer cells. High CTGF mRNA levels in the tissue samples correlated with better tumor differentiation (p < 0.03). In addition, patients whose tumors exhibited high CTGF mRNA levels (> onefold increase above normal controls) lived significantly longer than those whose tumors expressed low CTGF mRNA levels (none to onefold) (p < 0.04 multivariate analysis). Our present data indicate that CTGF, as a downstream mediator of TGFß, is overexpressed in connective tissue cells and to a lesser extent in pancreatic cancer cells. Because patients with high CTGF mRNA expression levels have a better prognosis, our findings indicate that the desmoplastic reaction provides a growth disadvantage for pancreatic cancer cells.

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

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. B Gudjonsson (1987) ArticleTitleCancer of the pancreas: 50 years of surgery Cancer 60 2284–2303 Occurrence Handle1:STN:280:BieC2M%2FmvVI%3D Occurrence Handle3326653

    CAS  PubMed  Google Scholar 

  2. GA Parker RW Postlethwait (1985) ArticleTitleThe continuing problem of carcinoma of the pancreas J. Surg. Oncol. 28 36–38 Occurrence Handle1:STN:280:BiqC3cblvVw%3D Occurrence Handle2578588

    CAS  PubMed  Google Scholar 

  3. National Cancer Institute. Annual Cancer Statistics Review 1973-1988 (NIH Publ. No. 91-2789), Bethesda, Department of Health and Human Services, 1991

  4. Swedish Cancer Registry. Cancer Incidence in Sweden 1988, Stockholm, National Board of Health and Welfare, 1991

  5. MR Arguedas GH Heudebert AA Stinnett et al. (2002) ArticleTitleBiliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a cost-effectiveness analysis Am. J. Gastroenterol. 97 898–904 Occurrence Handle12003425

    PubMed  Google Scholar 

  6. HJ Wanebo AS Glicksman MP Vezeridis et al. (2000) ArticleTitlePreoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer Arch. Surg. 135 81–87 Occurrence Handle10.1001/archsurg.135.1.81 Occurrence Handle1:STN:280:DC%2BD3c7gtVejug%3D%3D Occurrence Handle10636353

    Article  CAS  PubMed  Google Scholar 

  7. SR Bramhall JP Neoptolemus (1997) ArticleTitleAdjuvant chemotherapy in pancreatic cancer Int. J. Pancreatol. 21 59–63 Occurrence Handle1:CAS:528:DyaK2sXjtFemsLk%3D Occurrence Handle9127175

    CAS  PubMed  Google Scholar 

  8. B Farrow BM Evers (2002) ArticleTitleInflammation and the development of pancreatic cancer Surg. Oncol. 10 153–169 Occurrence Handle10.1016/S0960-7404(02)00015-4 Occurrence Handle12020670

    Article  PubMed  Google Scholar 

  9. Y Nishimura R Hosotani Y Shibamoto et al. (1997) ArticleTitleExternal and intra-operative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications Int. J. Radiat. Oncol. Biol. Phys. 39 39–49 Occurrence Handle10.1016/S0360-3016(97)00295-2 Occurrence Handle1:STN:280:ByiH2cvitVI%3D Occurrence Handle9300738

    Article  CAS  PubMed  Google Scholar 

  10. H Friess M Büchler M Kruger et al. (1992) ArticleTitleTreatment of duct carcinoma of the pancreas with the LH-RH analogue buserelin Pancreas 7 516–521 Occurrence Handle1:STN:280:By2A1czitFA%3D Occurrence Handle1513800

    CAS  PubMed  Google Scholar 

  11. Å Andrén-Sandberg D Hoem PL Backman (1999) ArticleTitleOther risk factors for pancreatic cancer: hormonal aspects Ann. Oncol. 10 131–135 Occurrence Handle10.1023/A:1008377928466 Occurrence Handle10436805

    Article  PubMed  Google Scholar 

  12. H Friess M Büchler C Beglinger et al. (1993) ArticleTitleLow-dose octreotide treatment is not effective in patients with advanced pancreatic cancer Pancreas 8 540–545 Occurrence Handle1:STN:280:ByuC3svmsVc%3D Occurrence Handle8302789

    CAS  PubMed  Google Scholar 

  13. HG Beger MW Büchler H Friess (1994) ArticleTitleChirurgische Ergebnisse und Indikation zu adjuvanten Massnahmen beim Pankreaskarzinom Chirurg 65 246–252 Occurrence Handle1:STN:280:ByuB1M7ksFw%3D Occurrence Handle7912665

    CAS  PubMed  Google Scholar 

  14. M Büchler H Friess KH Schultheiss et al. (1991) ArticleTitleA randomized controlled trial of adjuvant immunotherapy (murine monoclonal antibody 494/32) in resectable pancreatic cancer Cancer 68 1507–1512 Occurrence Handle1654194

    PubMed  Google Scholar 

  15. C Wenger V Ellenrieder B Alber et al. (1999) ArticleTitleExpression and differential regulation of connective tissue growth factor in pancreatic cancer cells Oncogene 18 1073–1080 Occurrence Handle10.1038/sj.onc.1202395 Occurrence Handle1:CAS:528:DyaK1MXhsVyiurY%3D Occurrence Handle10023684

    Article  CAS  PubMed  Google Scholar 

  16. RP Ryseck BH Macdonald MG Mattei et al. (1991) ArticleTitleStructure, mapping, and expression of fisp-12, a growth factor-inducible gene encoding a secreted cysteine-rich protein Cell Growth Differ. 2 225–233 Occurrence Handle1:CAS:528:DyaK3sXktVehurg%3D Occurrence Handle1888698

    CAS  PubMed  Google Scholar 

  17. EJ Battegay EW Raines RA Seifert et al. (1990) ArticleTitleTGF-ß induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop Cell 63 515–524 Occurrence Handle10.1016/0092-8674(90)90448-N Occurrence Handle1:CAS:528:DyaK3MXht1Sq Occurrence Handle2171777

    Article  CAS  PubMed  Google Scholar 

  18. K Frazier S Williams D Kothapalli et al. (1996) ArticleTitleStimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor J. Invest. Dermatol. 107 404–411 Occurrence Handle10.1111/1523-1747.ep12363389 Occurrence Handle1:CAS:528:DyaK28XlvVOnsrg%3D Occurrence Handle8751978

    Article  CAS  PubMed  Google Scholar 

  19. GR Grotendorst H Okochi N Hayashi (1996) ArticleTitleA novel transforming growth factor-ß response element controls the expression of the connective tissue growth factor gene Cell Growth Differ. 7 469–480 Occurrence Handle1:CAS:528:DyaK28XitFegt7k%3D Occurrence Handle9052988

    CAS  PubMed  Google Scholar 

  20. K Hishikawa BS Oemar FC Tanner et al. (1999) ArticleTitleConnective tissue growth factor induces apoptosis in human breast cancer cell line MCF-7 J. Biol. Chem. 274 37461–37466 Occurrence Handle10.1074/jbc.274.52.37461 Occurrence Handle1:CAS:528:DC%2BD3cXpsFGj Occurrence Handle10601320

    Article  CAS  PubMed  Google Scholar 

  21. A Koliopanos H Friess FF Mola Particledi et al. (2002) ArticleTitleConnective tissue growth factor gene expression alters tumor progression in esophageal cancer World J. Surg. 26 420–427 Occurrence Handle10.1007/s00268-001-0242-x Occurrence Handle11910473

    Article  PubMed  Google Scholar 

  22. BS Oemar A Werner J-M Garnier et al. (1997) ArticleTitleHuman connective tissue growth factor is expressed in advanced atherosclerotic lesions Circulation 95 831–839 Occurrence Handle1:STN:280:ByiB3cjksVI%3D Occurrence Handle9054739

    CAS  PubMed  Google Scholar 

  23. H Friess ZW Zhu FF Mola Particledi et al. (1999) ArticleTitleNerve growth factor and its high-affinity receptor in chronic pancreatitis Ann. Surg. 230 615–624 Occurrence Handle10.1097/00000658-199911000-00002 Occurrence Handle1:STN:280:DC%2BD3c%2FitlOnsg%3D%3D Occurrence Handle10561084

    Article  CAS  PubMed  Google Scholar 

  24. H Friess Z Lu Å Andrén-Sandberg et al. (1998) ArticleTitleModerate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer Ann. Surg. 228 780–787 Occurrence Handle10.1097/00000658-199812000-00009 Occurrence Handle1:STN:280:DyaK1M%2FnsFyhsg%3D%3D Occurrence Handle9860477

    Article  CAS  PubMed  Google Scholar 

  25. Z Zhu H Friess FF Mola Particledi et al. (1999) ArticleTitleNerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer J. Clin. Oncol. 17 2419–2428 Occurrence Handle1:STN:280:DC%2BD3c%2FjtVSgtg%3D%3D Occurrence Handle10561305

    CAS  PubMed  Google Scholar 

  26. H Friess XZ Guo P Berberat et al. (1998) ArticleTitleReduced KAI1 expression in pancreatic cancer is associated with lymph node and distant metastases Int. J. Cancer 79 349–355 Occurrence Handle10.1002/(SICI)1097-0215(19980821)79:4<349::AID-IJC7>3.0.CO;2-V Occurrence Handle1:CAS:528:DyaK1cXltVegs78%3D Occurrence Handle9699525

    Article  CAS  PubMed  Google Scholar 

  27. H Friess D Cantero H Graber et al. (1997) ArticleTitleEnhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis Gastroenterology 113 904–913 Occurrence Handle1:STN:280:ByiH3svgvFM%3D Occurrence Handle9287983

    CAS  PubMed  Google Scholar 

  28. FF Mola ParticleDi H Friess ME Martignoni et al. (1999) ArticleTitleConnective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis Ann. Surg. 230 63–71 Occurrence Handle10.1097/00000658-199907000-00010 Occurrence Handle10400038

    Article  PubMed  Google Scholar 

  29. FF Mola ParticleDi H Friess E Riesle et al. (2002) ArticleTitleConnective tissue growth factor is involved in pancreatic repair and tissue remodeling in human and rat acute necrotizing pancreatitis Ann. Surg. 235 60–67 Occurrence Handle10.1097/00000658-200201000-00008 Occurrence Handle11753043

    Article  PubMed  Google Scholar 

  30. DR Brigstock CL Steffen GY Kim et al. (1997) ArticleTitlePurification and characterization of novel heparin-binding growth factors in uterine secretory fluids: identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor J. Biol. Chem. 272 20275–20282 Occurrence Handle10.1074/jbc.272.32.20275 Occurrence Handle1:CAS:528:DyaK2sXltlGku7w%3D Occurrence Handle9242708

    Article  CAS  PubMed  Google Scholar 

  31. DW Hosmer S Lemeshow (2000) Applied Logistic Regression Wiley New York

    Google Scholar 

  32. MJ Norusis (1998) SPSS/PC+ User’s Guide EditionNumberVersion 8.0 SPSS Chicago

    Google Scholar 

  33. H Friess Y Yamanaka M Büchler et al. (1993) ArticleTitleEnhanced expression of transforming growth factor-ß isoforms in pancreatic cancer correlates with decreased survival Gastroenterology 105 1846–1856 Occurrence Handle1:CAS:528:DyaK2cXnsVCksA%3D%3D Occurrence Handle8253361

    CAS  PubMed  Google Scholar 

  34. J Kleeff T Ishiwata H Maruyama et al. (1999) ArticleTitleThe TGF-ß signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer Oncogene 18 5363–5372 Occurrence Handle10.1038/sj.onc.1202909 Occurrence Handle1:CAS:528:DyaK1MXms1Ohs7c%3D Occurrence Handle10498890

    Article  CAS  PubMed  Google Scholar 

  35. H Friess Y Yamanaka M Büchler et al. (1993) ArticleTitleEnhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression Cancer Res. 53 2704–2707 Occurrence Handle1:CAS:528:DyaK3sXltFCmurw%3D Occurrence Handle8389240

    CAS  PubMed  Google Scholar 

  36. J Kleeff M Korc (1998) ArticleTitleUp-regulation of transforming growth factor TGF-ß receptors by TGF-ß1 in COLO-357 cells J. Biol. Chem. 273 7495–7500 Occurrence Handle10.1074/jbc.273.13.7495 Occurrence Handle1:CAS:528:DyaK1cXit1elsr4%3D Occurrence Handle9516449

    Article  CAS  PubMed  Google Scholar 

  37. J Kleeff H Maruyama H Friess et al. (1999) ArticleTitleSmad-6 suppresses TGF-ß-induced growth inhibition in COLO-357 pancreatic cancer cells and is over-expressed in pancreatic cancer Biochem. Biophys. Res. Commun. 255 268–273 Occurrence Handle10.1006/bbrc.1999.0171 Occurrence Handle1:CAS:528:DyaK1MXhsVShsLk%3D Occurrence Handle10049697

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments.

This study was in part supported by the “Compagnia di San Paolo” Fund grant (Italy) (Oncology Program) awarded to P. Innocenti (grant 11583/23720) and by the DFG (Deutsche Forschungsgemeinschaft; grant SE 1095/1-1 awarded to P. Di Sebastiano and H. Friess). Dr. F.F. di Mola is a surgical resident whose research stay was supported by the University of Chieti, Italy. Dr. A. Gardini is a resident of the Department of General and Transplantation Surgery, University of Bologna, Italy, and his research stay was supported by the Italian Ministry of University.

Author information

Authors and Affiliations

  1. Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Mark Hartel M.D., Fabio F. di Mola M.D., Andrea Gardini M.D., Pierluigi Di Sebastiano M.D., Ahmed Guweidhi M.D., Thomas Giese M.D., Nathalia Giese M.D., Markus W. Büchler M.D. & Helmut Friess M.D.

  2. Institute of Pathology, University of Bern, Inselspital, Murtenstrasse 31 Sucher: 181 67 31, Postfach 62, CH-3010, Bern, Switzerland

    Arthur Zimmermann Ph.D.

  3. Department of General and Laparoscopic Surgery, University of Chieti, Via dei Vestini, 66100, Chieti, Italy

    Paolo Innocenti M.D.

Authors
  1. Mark Hartel M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio F. di Mola M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Gardini M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur Zimmermann Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierluigi Di Sebastiano M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmed Guweidhi M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paolo Innocenti M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Giese M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nathalia Giese M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Markus W. Büchler M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Helmut Friess M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helmut Friess M.D..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hartel, M., di Mola, F., Gardini, A. et al. Desmoplastic Reaction Influences Pancreatic Cancer Growth Behavior. World J. Surg. 28, 818–825 (2004). https://doi.org/10.1007/s00268-004-7147-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-004-7147-4

Keywords

Search

Navigation