Skip to main content

Advertisement

SpringerLink
Log in

Recruitment of Podoplanin Positive Cancer-Associated Fibroblasts in Metastatic Lymph Nodes Predicts Poor Prognosis in Pathological N2 Stage III Lung Adenocarcinoma

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Cancer-associated fibroblasts (CAFs) directly communicate with cancer cells and play important roles in cancer progression. Recent studies have reported that primary cancer tissue with podoplanin-expressing CAFs predicted a poorer outcome among stage I lung adenocarcinoma patients. However, whether podoplanin(+)-CAFs also can be recruited into metastatic lymph nodes and influence the prognosis remains unclear.

Methods

We selected 112 patients with pathological N2 stage III lung adenocarcinoma and examined the podoplanin expression of CAFs and their prognostic impact in primary and metastatic N2 lesions.

Results

Podoplanin(+)-CAFs were observed in 61 (54.5 %) primary sites and 44 (39.3 %) metastatic lymph nodes. Podoplanin(+)-CAFs were found at metastatic lymph nodes in 33 (54.1 %) primary podoplanin-positive and 11 (21.6 %) primary podoplanin-negative sites. These findings suggest a significant positive correlation in podoplanin expression in CAFs between pairs of primary and metastatic lesions (P < 0.001). The difference in the overall survival of patients with podoplanin-positive/negative CAFs in their primary lesion was not correlated (P = 0.927). In contrast, patients with podoplanin(+)-CAFs in metastatic lymph nodes had a shorter overall survival than those without podoplanin(+)-CAFs (P = 0.003). In multivariate analyses, podoplanin(+)-CAFs in metastatic lymph nodes were a significantly independent risk factor for a poor outcome (P = 0.007).

Conclusions

Our study indicated that podoplanin(+)-CAFs in metastatic lymph nodes was a significant prognostic factor for overall survival among pathological N2 stage III adenocarcinoma patients.

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

Similar content being viewed by others

References

  1. Baglole CJ, Ray DM, Bernstein SH, et al. More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Invest. 2006;35:297–325.

    Article  PubMed  CAS  Google Scholar 

  2. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1:46–54.

    Article  PubMed  CAS  Google Scholar 

  3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  4. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392–401.

    Article  PubMed  CAS  Google Scholar 

  5. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  PubMed  CAS  Google Scholar 

  6. Morrissey C, Vessella RL. The role of tumor microenvironment in prostate cancer bone metastasis. J Cell Biochem. 2007;101:873–86.

    Article  PubMed  CAS  Google Scholar 

  7. Patocs A, Zhang L, Xu Y, et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med. 2007;357:2543–51.

    Article  PubMed  CAS  Google Scholar 

  8. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006;1:119–50.

    Article  PubMed  CAS  Google Scholar 

  9. Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol. 2004;48:509–17.

    Article  PubMed  CAS  Google Scholar 

  10. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.

    Article  PubMed  CAS  Google Scholar 

  11. Pietras K, Pahler J, Bergers G, et al. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008;5:e19.

    Article  PubMed  Google Scholar 

  12. Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6:17–32.

    Article  PubMed  CAS  Google Scholar 

  13. Cui L, Ohuchida K, Mizumoto K, et al. Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(−) cancer cells. PLoS One. 2010;5:e12121.

    Google Scholar 

  14. Nakao M, Ishii G, Nagai K, et al. Prognostic significance of carbonic anhydrase IX expression by cancer-associated fibroblasts in lung adenocarcinoma. Cancer. 2009;115:2732–43.

    Article  PubMed  CAS  Google Scholar 

  15. Bremnes RM, Donnem T, Al-Saad S, et al. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol. 2011;6:209–17.

    Google Scholar 

  16. Wicki A, Christofori G. The potential role of podoplanin in tumour invasion. Br J Cancer. 2007;96:1–5.

    Article  PubMed  CAS  Google Scholar 

  17. Kawase A, Ishii G, Nagai K, et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008;123:1053–9.

    Article  PubMed  CAS  Google Scholar 

  18. Hoshino A, Ishii G, Ito T, et al. Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation. Cancer Res. 2011;71:4769–79.

    Google Scholar 

  19. Aishima S, Nishihara Y, Iguchi T, et al. Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma. Mod Pathol. 2008;21:256–64.

    Article  PubMed  CAS  Google Scholar 

  20. Coghlin C, Murray GI. Current and emerging concepts in tumour metastasis. J Pathol. 2010;222:1–15.

    Google Scholar 

  21. Vered M, Dayan D, Yahalom R, et al. Cancer-associated fibroblasts and epithelial-mesenchymal transition in metastatic oral tongue squamous cell carcinoma. Int J Cancer. 2010;127:1356–62.

    Google Scholar 

  22. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–14.

    Article  PubMed  Google Scholar 

  23. Travis WD, Brambilla E, Müller-Hermelink HK, et al., editors. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.

    Google Scholar 

  24. Kumar V, Abbas AK, Fausto N. Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: W.B. Saunders; 2004.

    Google Scholar 

  25. Ishii G, Sangai T, Sugiyama K, et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells. 2005;23:699–706.

    Article  PubMed  CAS  Google Scholar 

  26. Duda DG, Duyverman AM, Kohno M, et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci USA. 2010;107:21677–82.

    Google Scholar 

  27. Xie Q, Chen L, Fu K, et al. Podoplanin (d2-40): a new immunohistochemical marker for reactive follicular dendritic cells and follicular dendritic cell sarcomas. Int J Clin Exp Pathol. 2008;1:276–84.

    PubMed  CAS  Google Scholar 

  28. Ohta Y, Shimizu Y, Minato H, et al. Results of initial operations in non-small cell lung cancer patients with single-level N2 disease. Ann Thorac Surg. 2006;81:427–33.

    Article  PubMed  Google Scholar 

  29. Nakagiri T, Sawabata N, Funaki S, et al. Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2011;12:733–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank Mr. Shogo Nomura for statistical advice and Mr. Shinya Yanagi for technical support. This work was supported by the Grant-in-Aid for Cancer Research (19-10) from the Ministry of Health, Labor, and Welfare Programs; the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control; Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation.

Author information

Authors and Affiliations

  1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Shinya Neri, Genichiro Ishii, Tetsuhiko Taira & Atsushi Ochiai

  2. Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Shinya Neri, Tetsuhiko Taira, Tomoyuki Hishida, Junji Yoshida, Mitsuyo Nishimura & Kanji Nagai

Authors
  1. Shinya Neri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Genichiro Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tetsuhiko Taira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoyuki Hishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junji Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mitsuyo Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kanji Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Atsushi Ochiai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Genichiro Ishii or Atsushi Ochiai.

Additional information

This work was supported by the Grant-in-Aid for Cancer Research (19-10) from the Ministry of Health, Labor, and Welfare Programs; the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control; Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 56 kb)

Supplementary material 2 (DOC 55 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neri, S., Ishii, G., Taira, T. et al. Recruitment of Podoplanin Positive Cancer-Associated Fibroblasts in Metastatic Lymph Nodes Predicts Poor Prognosis in Pathological N2 Stage III Lung Adenocarcinoma. Ann Surg Oncol 19, 3953–3962 (2012). https://doi.org/10.1245/s10434-012-2421-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-012-2421-4

Keywords

Search

Navigation