Tumor Biology

, Volume 34, Issue 1, pp 131–137 | Cite as

Biglycan expression and clinical outcome in patients with pancreatic adenocarcinoma

  • Giuseppe Aprile
  • Claudio Avellini
  • Michele Reni
  • Micol Mazzer
  • Luisa Foltran
  • Diego Rossi
  • Stefano Cereda
  • Emiliana Iaiza
  • Gianpiero Fasola
  • Andrea Piga
Research Article


Conflicting results have been reported on the role of extracellular matrix (ECM) proteins in pancreatic cancer. Preclinical studies suggest that the overexpression of biglycan (proteoglycan-I, PG-I), a leucine-rich protein of the ECM, may induce growth arrest of pancreatic cancer cells. The aim of this study was to assess the prognostic role of biglycan expression in pancreatic cancer. We also evaluated MIB-1 and COX-2 expressions (as potential markers of growth and aggressiveness) to better characterize the biology of the tumors. The classical pathological parameters (grading, desmoplasia, perineural, or vascular invasion) as well as molecular determinants of prognosis were examined. MIB-1 (a proliferative index associated with prognosis in most tumors), COX-2, and PG-I expressions were detected by immunohistochemistry and immunofluorescence on tissue samples from 53 patients with pancreatic cancer and reviewed by two independent pathologists. To verify PG-I expression, three rabbit sera (LF104, LF112, and LF121 from NIH, Bethesda, MA, US) were tested. Logrank test and Cox’s model were applied for statistical analysis. Out of 53 patients, 40 had stage III and IV pancreatic cancer. Fourteen patients did not express any of the PG-I epitopes. The patients who expressed at least two PG-I epitopes had shorter survival compared to those with single epitope or lacking any expression (28 vs 44 weeks, P = 0.0021). The MIB-1 higher expression predicted shorter survival (25 vs 41 weeks, P = 0.0059). The other parameters were not associated with clinical outcome. Multivariate analyses confirmed PG-I expression and MIB-1 as independent negative prognostic factors. Patients who presented PG-I expression in the ECM had the worse prognosis compared to those who did not. Our results are not in contrast with the hypothesis that ECM proteins are a potential barrier to metastatic spread in localized pancreatic cancer. Rather, we underline the complexity of tumor–stroma interactions in the advanced stage of cancer and the need of further study.


Pancreatic cancer Biglycan Survival 


  1. 1.
    Bhowmick NA, Moses HL. Tumor–stroma interactions. Curr Opin Genet Dev. 2005;15:97–101.PubMedCrossRefGoogle Scholar
  2. 2.
    Cheng N, Bhowmick NA, Chytil A, et al. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene. 2005;24:5053–68.PubMedCrossRefGoogle Scholar
  3. 3.
    Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res. 2002;8:2912–23.PubMedGoogle Scholar
  4. 4.
    Auvinen P, Parkkinen J, Tammi M, et al. Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol. 2000;156:529–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Barlow J, Yandell D, Weaver D, Casey T, Plaut K. Higher stromal expression of transforming growth factor-beta type II receptors is associated with poorer prognosis breast tumors. Breast Cancer Res Treat. 2003;79:149–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Bergamaschi A, Tagliabue E, Sorlie T, et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol. 2008;214:357–67.PubMedCrossRefGoogle Scholar
  7. 7.
    Ricciardelli C, Brooks JH, Suwiwat S, et al. Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer. Clin Cancer Res. 2002;8:1054–60.PubMedGoogle Scholar
  8. 8.
    Smith K, Fox SB, Whitehouse R, Taylor M, Greenall M, Clarke J, et al. Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival. Ann Oncol. 1999;10:707–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res. 2008;149:319–28.PubMedCrossRefGoogle Scholar
  10. 10.
    Okegawa T, Pong RC, Li Y, Hsieh JT. The role of cell adhesion molecule in cancer progression and its application in cancer therapy. Acta Biochim Pol. 2004;51:445–57.PubMedGoogle Scholar
  11. 11.
    Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10:415–27.PubMedCrossRefGoogle Scholar
  12. 12.
    Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001;19:3447–55.PubMedGoogle Scholar
  13. 13.
    Farrow B, Rychahou P, O'Connor KL, Evres BM. Butyrate inhibits pancreatic cancer invasion. J Gastrointest Surg. 2003;7:864–70.PubMedCrossRefGoogle Scholar
  14. 14.
    Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer. 2005;41:2213–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Johnson SK, Ramani VC, Hennings L, Haun RS. Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin. Cancer. 2007;109:1811–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Köninger J, Giese T, di Mola FF, et al. Pancreatic tumor cells influence the composition of the extracellular matrix. Biochem Biophys Res Commun. 2004;322:943–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Sawai H, Okada Y, Funahashi H, Takahashi H, Matsuo Y, Yasuda A, et al. Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. J Surg Res. 2008;144:117–23.PubMedCrossRefGoogle Scholar
  18. 18.
    Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology. 2007;7:423–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Weber CK, Sommer G, Michl P, Fensterer H, Weimer M, Gansauge F, et al. Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology. 2001;121:657–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Hill R, Li Y, Tran LM, et al. Cell intrinsic role of Cox-2 in pancreatic cancer development. Mol Cancer Ther 2012 (in press)Google Scholar
  21. 21.
    Gu X, Ma Y, Xiao J, Zheng H, Song C, Gong Y, et al. Up-regulated biglycan expression correlates with the malignancy in human colorectal cancers. Clin Exp Med. 2011. doi: 10.1007/s10238-011-0155-4.
  22. 22.
    Wang B, Li GX, Zhang SG, et al. Biglycan expression correlates with aggressiveness and poor prognosis of gastric cancer. Exp Biol Med (Maywood). 2011. doi: 10.1258/ebm.2011.011124.
  23. 23.
    Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V. Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer. Oncology. 2006;70:255–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Boeck S, Hinke A, Wilkowski R, Heinemann V. Importance of performance status for treatment outcome in advanced pancreatic cancer. World J Gastroenterol. 2007;13:224–7.PubMedGoogle Scholar
  25. 25.
    Ferrone CR, Finkelstein D, Thayer SP, Muzikansky A, Fernandez-del Castillo C, Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol. 2006;24:2897–902.PubMedCrossRefGoogle Scholar
  26. 26.
    Gupta D, Lis CG, Grutsch JF. The European organization for research and treatment of cancer quality of life questionnaire: implications for prognosis in pancreatic cancer. Int J Gastrointest Cancer. 2006;37:65–73.PubMedCrossRefGoogle Scholar
  27. 27.
    Han SS, Jang JY, Kim SW, Kim WH, Lee KU, Park YH. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006;32:271–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Katz MH, Hwang R, Fleming JB, Evans DB. Tumor-node-metastasis staging of pancreatic adenocarcinoma. CA Cancer J Clin. 2008;58:111–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Krishnan S, Rana V, Janjan NA, et al. Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation. Cancer. 2006;107:2589–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Moon HJ, An JY, Heo JS, Choi SH, Joh JW, Kim YI. Predicting survival after surgical resection for pancreatic ductal adenocarcinoma. Pancreas. 2006;32:37–43.PubMedCrossRefGoogle Scholar
  31. 31.
    Park JK, Yoon YB, Kim YT, Ryu JK, Yoon WJ, Lee SH. Survival and prognostic factors of unresectable pancreatic cancer. J Clin Gastroenterol. 2008;42:86–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Sezgin C, Karabulut B, Uslu R, Sanli UA, Goksel G, Yuzer Y, et al. Gemcitabine treatment in patients with inoperable locally advanced/metastatic pancreatic cancer and prognostic factors. Scand J Gastroenterol. 2005;40:1486–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Tani M, Kawai M, Terasawa H, Ina S, Hirono S, Shimamoto T, et al. Prognostic factors for long-term survival in patients with locally invasive pancreatic cancer. J Hepatobiliary Pancreat Surg. 2007;14:545–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Tonini G, Pantano F, Vincenzi B, Gabbrielli A, Coppola R, Santini D. Molecular prognostic factors in patients with pancreatic cancer. Expert Opin Ther Targets. 2007;11:1553–69.PubMedCrossRefGoogle Scholar
  35. 35.
    Cao D, Zhang Q, Wu LS, Salaria SN, Winter JW, Hruban RH, et al. Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases. Mod Pathol. 2007;20:570–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, et al. Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol. 2006;13:933–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Juuti A, Louhimo J, Nordling S, Ristimäki A, Haglund C. Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer. J Clin Pathol. 2006;59:382–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Link BC, Reichelt U, Schreiber M, et al. Prognostic implications of netrin-1 expression and its receptors in patients with adenocarcinoma of the pancreas. Ann Surg Oncol. 2007;14:2591–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Maeda S, Shinchi H, Kurahara H, et al. Clinical significance of midkine expression in pancreatic head carcinoma. Br J Cancer. 2007;97:405–11.PubMedCrossRefGoogle Scholar
  40. 40.
    Matsubayashi H, Infante JR, Winter J, et al. Tumor COX-2 expression and prognosis of patients with resectable pancreatic cancer. Cancer Biol Ther. 2007;6:1569–75.PubMedCrossRefGoogle Scholar
  41. 41.
    Sasada T, Azuma K, Hirai T, et al. Prognostic significance of the immediate early response gene X-1 (IEX-1) expression in pancreatic cancer. Ann Surg Oncol. 2008;15:609–17.PubMedCrossRefGoogle Scholar
  42. 42.
    Skalicky DA, Kench JG, Segara D, et al. Cyclin E expression and outcome in pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15:1941–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Sun HC, Qiu ZJ, Liu J, Sun J, Jiang T, Huang KJ, et al. Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol. 2007;30:1359–67.PubMedGoogle Scholar
  44. 44.
    Tao J, Xiong J, Li T, Yang Z, Li X, Li K, et al. Correlation between protein expression of PTEN in human pancreatic cancer and the proliferation, infiltration, metastasis and prognosis. J Huazhong Univ Sci Technolog Med Sci. 2006;26:444–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Furuyama K, Doi R, Mori T, Furuyama K, Doi R, Mori T, et al. Clinical significance of focal adhesion kinase in resectable pancreatic cancer. World J Surg. 2006;30:219–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25:319–25.PubMedCrossRefGoogle Scholar
  47. 47.
    Bland MJ, Altman DJ. Logrank test. BMJ. 2004;328:1073.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Giuseppe Aprile
    • 1
  • Claudio Avellini
    • 2
  • Michele Reni
    • 3
  • Micol Mazzer
    • 1
  • Luisa Foltran
    • 1
  • Diego Rossi
    • 2
  • Stefano Cereda
    • 3
  • Emiliana Iaiza
    • 1
  • Gianpiero Fasola
    • 1
  • Andrea Piga
    • 4
  1. 1.Department of OncologyUniversity Hospital “S Maria della Misericordia” of UdineUdineItaly
  2. 2.Department of PathologyUniversity Hospital “S Maria della Misericordia” of UdineUdineItaly
  3. 3.Department of OncologySan Raffaele University-HospitalMilanItaly
  4. 4.Department of OncologyOspedale Oncologico A BusincoCagliariItaly

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