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.
Similar content being viewed by others
References
B Gudjonsson (1987) ArticleTitleCancer of the pancreas: 50 years of surgery Cancer 60 2284–2303 Occurrence Handle1:STN:280:BieC2M%2FmvVI%3D Occurrence Handle3326653
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
National Cancer Institute. Annual Cancer Statistics Review 1973-1988 (NIH Publ. No. 91-2789), Bethesda, Department of Health and Human Services, 1991
Swedish Cancer Registry. Cancer Incidence in Sweden 1988, Stockholm, National Board of Health and Welfare, 1991
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
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
SR Bramhall JP Neoptolemus (1997) ArticleTitleAdjuvant chemotherapy in pancreatic cancer Int. J. Pancreatol. 21 59–63 Occurrence Handle1:CAS:528:DyaK2sXjtFemsLk%3D Occurrence Handle9127175
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
DW Hosmer S Lemeshow (2000) Applied Logistic Regression Wiley New York
MJ Norusis (1998) SPSS/PC+ User’s Guide EditionNumberVersion 8.0 SPSS Chicago
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
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
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
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
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
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
Corresponding author
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00268-004-7147-4