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Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer

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Abstract

While cancer research has been focused on tumor cells for many years, evidence is growing that the tumor stroma and in particular cancer-associated fibroblasts (CAFs) in particular play essential roles in the progression of human malignant disease. In human lung cancer, CAFs expressing the transmembrane protein podoplanin were shown to have significant influence on the patients’ prognosis. In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs in a large series of patients with invasive breast cancer. Podoplanin expression was evaluated immunohistochemically in 367 breast cancers. Tumors with ≥10% distinct podoplanin staining were considered as positive (CAF+). Cytoplasmic podoplanin expression of tumor cells was considered as positive when ≥5% of tumor cells showed a distinct podoplanin expression. In normal breast tissue, no podoplanin-expressing fibrocytes were found. Thirty-three patients (9%) with breast cancer showed podoplanin expression in CAFs. In 28 patients (8%), a podoplanin expression in tumor cells was observed. A strong negative correlation of CAF+ with estrogen receptor status (p < 0.001), and a significant association with higher histological grading (p < 0.001) was seen. In multivariable analysis, CAFs+ was an independent prognostic factor for disease free (1.78 Hazard ratio; p = 0.026) and overall survival (2.304 Hazard ratio; p = 0.002) in patients with breast cancer. Podoplanin-expressing CAFs contribute to the prognosis of invasive breast cancer, indicating a highly aggressive subgroup. CAFs may present a highly selective target for anti-cancer therapies in patients with invasive breast cancer.

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References

  1. Birner P, Oberhuber G, Stani J, Reithofer C, Samonigg H, Hausmaninger H, Kubista E, Kwasny W, Kandioler-Eckersberger D, Gnant M, Jakesz R (2001) Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 7:1669–1675

    PubMed  CAS  Google Scholar 

  2. Birner P, Obermair A, Schindl M, Kowalski H, Breitenecker G, Oberhuber G (2001) Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. Clin Cancer Res 7:93–97

    PubMed  CAS  Google Scholar 

  3. Breiteneder-Geleff S, Soleiman A, Horvat R, Amann G, Kowalski H, Kerjaschki D (1999) Podoplanin—a specific marker for lymphatic endothelium expressed in angiosarcoma. Verh Dtsch Ges Pathol 83:270–275

    PubMed  CAS  Google Scholar 

  4. Elston CW, Ellis IO (2002) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 41:154–161. doi:1489_2[pii]

    Article  PubMed  CAS  Google Scholar 

  5. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795. doi:10.1200/JCO.2009.25.6529

    Article  PubMed  Google Scholar 

  6. Hasebe T, Sasaki S, Imoto S, Ochiai A (2000) Proliferative activity of intratumoral fibroblasts is closely correlated with lymph node and distant organ metastases of invasive ductal carcinoma of the breast. Am J Pathol 156:1701–1710. doi:10.1016/S0002-9440(10)65041-9

    Article  PubMed  CAS  Google Scholar 

  7. Hay ED, Zuk A (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 26:678–690. doi:0272-6386(95)90610-X[pii]

    Article  PubMed  CAS  Google Scholar 

  8. Hofheinz RD, al-Batran SE, Hartmann F, Hartung G, Jager D, Renner C, Tanswell P, Kunz U, Amelsberg A, Kuthan H, Stehle G (2003) Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26:44–48. doi:10.1159/000069863ONK26044[pii]

    Article  PubMed  CAS  Google Scholar 

  9. Hoshino A, Ishii G, Ito T, Aoyagi K, Ohtaki Y, Nagai K, Sasaki H, Ochiai A (2011) Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res 71:4769–4779. doi:10.1158/0008-5472.CAN-10-3228

    Article  PubMed  CAS  Google Scholar 

  10. Jakesz R, Hausmaninger H, Haider K, Kubista E, Samonigg H, Gnant M, Manfreda D, Tschurtschenthaler G, Kolb R, Stierer M, Fridrik M, Mlineritsch B, Steindorfer P, Mittlbock M, Steger G (1999) Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol 17:1701–1709

    PubMed  CAS  Google Scholar 

  11. Jakesz R, Hausmaninger H, Samonigg H, Kubista E, Haider K, Mlineritsch B, Schmid M, Tausch C, Reiner G, Renner K, Stierer M, Jatzko G, Hofbauer F, Fridrik M, Schennach W, Sevelda P, Dadak C, Haid A, Scholz R, Lenzhofer P, Steindorfer P, Berger A, Mischinger HJ (1998) Therapy studies of the Austrian Breast Cancer Group (ABC). Zentralbl Chir 123(Suppl 5):28–32

    PubMed  Google Scholar 

  12. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401. doi:nrc1877[pii]10.1038/nrc1877

    Article  PubMed  CAS  Google Scholar 

  13. Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, Hishida T, Nishimura M, Yoshida J, Suzuki K, Ochiai A (2008) Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer 123:1053–1059. doi:10.1002/ijc.23611

    Article  PubMed  CAS  Google Scholar 

  14. Kiely BE, Soon YY, Tattersall MH, Stockler MR (2011) How long have I got? Estimating typical, best-case, and worst-case scenarios for patients starting first-line chemotherapy for metastatic breast cancer: a systematic review of recent randomized trials. J Clin Oncol 29:456–463. doi:10.1200/JCO.2010.30.2174

    Article  PubMed  Google Scholar 

  15. Kim JB, Stein R, O’Hare MJ (2005) Tumour-stromal interactions in breast cancer: the role of stroma in tumourigenesis. Tumour Biol 26:173–185. doi:86950[pii]10.1159/000086950

    Article  PubMed  Google Scholar 

  16. Kimura N, Kimura I (2005) Podoplanin as a marker for mesothelioma. Pathol Int 55:83–86. doi:10.1111/j.1440-1827.2005.01791.x

    Article  PubMed  CAS  Google Scholar 

  17. Kitano H, Kageyama S, Hewitt SM, Hayashi R, Doki Y, Ozaki Y, Fujino S, Takikita M, Kubo H, Fukuoka J (2010) Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch Pathol Lab Med 134:1520–1527. doi:10.1043/2009-0114-OA.1

    PubMed  CAS  Google Scholar 

  18. Kreppel M, Scheer M, Drebber U, Ritter L, Zoller JE (2010) Impact of podoplanin expression in oral squamous cell carcinoma: clinical and histopathologic correlations. Virchows Arch 456:473–482. doi:10.1007/s00428-010-0915-7

    Article  PubMed  CAS  Google Scholar 

  19. Olsen CJ, Moreira J, Lukanidin EM, Ambartsumian NS (2010) Human mammary fibroblasts stimulate invasion of breast cancer cells in a three-dimensional culture and increase stroma development in mouse xenografts. BMC Cancer 10:444. doi:10.1186/1471-2407-10-444

    Article  PubMed  Google Scholar 

  20. Potenta S, Zeisberg E, Kalluri R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99:1375–1379. doi:10.1038/sj.bjc.6604662

    Article  PubMed  CAS  Google Scholar 

  21. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, McLendon RE, Pegram CN, Provenzale JM, Quinn JA, Rich JN, Vredenburgh JJ, Desjardins A, Gururangan S, Badruddoja M, Dowell JM, Wong TZ, Zhao XG, Zalutsky MR, Bigner DD (2006) Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol 24:115–122. doi:10.1200/JCO.2005.03.4082

    Article  PubMed  CAS  Google Scholar 

  22. Schemper M, Smith TL (1996) A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343–346

    Article  PubMed  CAS  Google Scholar 

  23. Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S (2001) Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res 21:2351–2355

    PubMed  CAS  Google Scholar 

  24. Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, Divgi CR, Hanson LH, Mitchell P, Gansen DN, Larson SM, Ingle JN, Hoffman EW, Tanswell P, Ritter G, Cohen LS, Bette P, Arvay L, Amelsberg A, Vlock D, Rettig WJ, Old LJ (2003) A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 9:1639–1647

    PubMed  CAS  Google Scholar 

  25. Shekhar MP, Werdell J, Santner SJ, Pauley RJ, Tait L (2001) Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. Cancer Res 61:1320–1326

    PubMed  CAS  Google Scholar 

  26. Shibahara J, Kashima T, Kikuchi Y, Kunita A, Fukayama M (2006) Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch 448:493–499. doi:10.1007/s00428-005-0133-x

    Article  PubMed  CAS  Google Scholar 

  27. Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282:25993–26001. doi:10.1074/jbc.M702327200

    Article  PubMed  CAS  Google Scholar 

  28. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454. doi:10.1038/nrc822nrc822[pii]

    Article  PubMed  CAS  Google Scholar 

  29. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145. doi:10.1200/JCO.2006.09.2775

    Article  PubMed  CAS  Google Scholar 

  30. Yamanashi T, Nakanishi Y, Fujii G, Akishima-Fukasawa Y, Moriya Y, Kanai Y, Watanabe M, Hirohashi S (2009) Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma. Oncology 77:53–62. doi:10.1159/000226112

    Article  PubMed  CAS  Google Scholar 

  31. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67:10123–10128. doi:10.1158/0008-5472.CAN-07-3127

    Article  PubMed  CAS  Google Scholar 

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The Authors declare no disclosure of any commercial interest.

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Authors and Affiliations

  1. Department of Surgery, General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Sebastian F. Schoppmann, Raimund Jakesz, Michael Gnant, Peter Dubsky & Bettina Jesch

  2. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Anna Berghoff

  3. University of Applied Sciences, FH Campus, Krems, Austria

    Carina Dinhof

  4. Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria

    Harald Heinzl

  5. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

    Peter Birner

Authors
  1. Sebastian F. Schoppmann
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  2. Anna Berghoff
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  3. Carina Dinhof
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  4. Raimund Jakesz
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  9. Peter Birner
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Correspondence to Sebastian F. Schoppmann.

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Schoppmann, S.F., Berghoff, A., Dinhof, C. et al. Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer. Breast Cancer Res Treat 134, 237–244 (2012). https://doi.org/10.1007/s10549-012-1984-x

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  • DOI: https://doi.org/10.1007/s10549-012-1984-x

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