Skip to main content

Advertisement

SpringerLink
Log in

Stromal collagen type VI associates with features of malignancy and predicts poor prognosis in salivary gland cancer

  • Original Paper
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Collagen Type VI (COLVI) is an extracellular matrix protein that is upregulated in various solid tumours during tumour progression and has been shown to stimulate proliferation, suppress apoptosis and promote invasion and metastasis. It has also been described as a mediator of chemotherapy resistance and as a therapeutic target in preclinical cancer models. Here, we aimed to analyse the prognostic role of COLVI in salivary gland cancer (SGC).

Methods

Stromal COLVI protein expression was assessed in primary SGC specimens of 91 patients using immunohistochemistry (IHC). The IHC expression patterns obtained were subsequently correlated with various survival and clinicopathological features, including Ki-67 and p53 expression.

Results

We found that COLVI was expressed in all SGC specimens. High expression was found to be associated with features of malignancy such as high histologic grades, advanced and invasive T stages and metastatic lymph node involvement (p < 0.05 for all variables). COLVI expression was also found to correlate with both Ki-67 and p53 expression (p < 0.01). We found that high COLVI expression predicted a significantly inferior 5-year overall survival (38.3%, 55.1% and 93.8%; p = 0.002) and remained a significant predictor of prognosis in a multivariate Cox regression analysis (hazard ratio, 2.62; 95% confidence interval, 1.22–5.61; p = 0.013). In all low-risk subgroups COLVI expression identified patients with an adverse outcome. Patients receiving adjuvant radiotherapy had a poor survival when expressing high levels of COLVI.

Conclusions

Our data indicate that stromal COLVI expression associates with key features of malignancy, represents a novel independent prognostic factor and may affect response to radiotherapy in SGC. Although our results warrant validation in an independent cohort, assessing stromal COLVI expression may be suitable for future diagnostic and therapeutic decision making in patients with SGC.

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

Similar content being viewed by others

References

  1. J.W. Everson, P. Auclair, D.R. Gnepp, A.K. El-Naggar, in WHO Classification of Head and Neck Tumours. Tumours of the salivary glands (IARCPress, 2005)

  2. V.V. Poorten, A. Hart, T. Vauterin, G. Jeunen, J. Schoenaers, M. Hamoir, A. Balm, E. Stennert, O. Guntinas-Lichius, P. Delaere, Prognostic index for patients with parotid carcinoma: International external validation in a Belgian-German database. Cancer 115, 540–550 (2009). https://doi.org/10.1002/cncr.24015

    Article  PubMed  Google Scholar 

  3. H. Luukkaa, P. Klemi, I. Leivo, T. Vahlberg, R. Grenman, Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: An evaluation of 212 cases. Acta Oncol 45, 669–675 (2006). https://doi.org/10.1080/02841860500543208

    Article  PubMed  Google Scholar 

  4. D. Pedersen, J. Overgaard, H. Søgaard, O. Elbrønd, M. Overgaard, Malignant parotid tumors in 110 consecutive patients: Treatment results and prognosis. Laryngoscope 102, 1064-1069 (1992). https://doi.org/10.1288/00005537-199209000-00019

    Article  Google Scholar 

  5. W.M. Mendenhall, C.G. Morris, R.J. Amdur, J.W. Werning, D.B. Villaret, Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103, 2544–2550 (2005). https://doi.org/10.1002/cncr.21083

    Article  PubMed  Google Scholar 

  6. M. Nagliati, A. Bolner, V. Vanoni, L. Tomio, G. Lay, R. Murtas, M.A. Deidda, A. Madeddu, E. Delmastro, R. Verna, P. Gabriele, M. Amichetti, Surgery and radiotherapy in the treatment of malignant parotid tumors: A retrospective multicenter study. Tumori 95, 442–448 (2009)

    Article  PubMed  Google Scholar 

  7. U. Mahmood, M. Koshy, O. Goloubeva, M. Suntharalingam, Adjuvant radiation therapy for high-grade and/or locally advanced major salivary gland tumors. Arch Otolaryngol Head Neck Surg 137, 1025–1030 (2011). https://doi.org/10.1001/archoto.2011.158

    Article  PubMed  Google Scholar 

  8. S.A. Laurie, A.L. Ho, M.G. Fury, E. Sherman, D.G. Pfister, Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: A systematic review. Lancet Oncol 12, 815–824 (2011). https://doi.org/10.1016/s1470-2045(10)70245-x

    Article  PubMed  CAS  Google Scholar 

  9. A. Amini, T.V. Waxweiler, J.V. Brower, B.L. Jones, J.D. McDermott, D. Raben, D. Ghosh, D.W. Bowles, S.D. Karam, Association of adjuvant chemoradiotherapy vs radiotherapy alone with survival in patients with resected major salivary gland carcinoma: Data from the national cancer data base. JAMA Otolaryngol Head Neck Surg 142, 1100–1110 (2016). https://doi.org/10.1001/jamaoto.2016.2168

    Article  PubMed  Google Scholar 

  10. M. Cescon, F. Gattazzo, P. Chen, P. Bonaldo, Collagen VI at a glance. J Cell Sci 128, 3525–3531 (2015). https://doi.org/10.1242/jcs.169748

    Article  PubMed  CAS  Google Scholar 

  11. S.K. Gara, P. Grumati, A. Urciuolo, P. Bonaldo, B. Kobbe, M. Koch, M. Paulsson, R. Wagener, Three novel collagen VI chains with high homology to the alpha3 chain. J Biol Chem 283, 10658–10670 (2008). https://doi.org/10.1074/jbc.M709540200

    Article  PubMed  CAS  Google Scholar 

  12. P. Chen, M. Cescon, P. Bonaldo, Collagen VI in cancer and its biological mechanisms. Trends Mol Med 19, 410–417 (2013). https://doi.org/10.1016/j.molmed.2013.04.001

    Article  PubMed  CAS  Google Scholar 

  13. L. Angenendt, S. Reuter, D. Kentrup, A.S. Benk, F. Neumann, J. Huve, A.C. Martens, C. Schwoppe, T. Kessler, L.H. Schmidt, T. Sauer, C. Brand, J.H. Mikesch, G. Lenz, R.M. Mesters, C. Muller-Tidow, W. Hartmann, E. Wardelmann, D. Neri, W.E. Berdel, C. Roesli, C. Schliemann, An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia. Leukemia 32, 510–519 (2018). https://doi.org/10.1038/leu.2017.208

    Article  PubMed  CAS  Google Scholar 

  14. J. Park, P.E. Scherer, Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 122, 4243–4256 (2012). https://doi.org/10.1172/JCI63930

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. P. Iyengar, T.P. Combs, S.J. Shah, V. Gouon-Evans, J.W. Pollard, C. Albanese, L. Flanagan, M.P. Tenniswood, C. Guha, M.P. Lisanti, R.G. Pestell, P.E. Scherer, Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene 22, 6408–6423 (2003). https://doi.org/10.1038/sj.onc.1206737

    Article  PubMed  CAS  Google Scholar 

  16. W.K. You, P. Bonaldo, W.B. Stallcup, Collagen VI ablation retards brain tumor progression due to deficits in assembly of the vascular basal lamina. Am J Pathol 180, 1145–1158 (2012). https://doi.org/10.1016/j.ajpath.2011.11.006

    Article  PubMed  PubMed Central  Google Scholar 

  17. I.H. Cheng, Y.C. Lin, E. Hwang, H.T. Huang, W.H. Chang, Y.L. Liu, C.Y. Chao, Collagen VI protects against neuronal apoptosis elicited by ultraviolet irradiation via an Akt/phosphatidylinositol 3-kinase signaling pathway. Neuroscience 183, 178–188 (2011). https://doi.org/10.1016/j.neuroscience.2011.03.057

    Article  PubMed  CAS  Google Scholar 

  18. J. Han, J.C. Daniel, Biosynthesis of type VI collagen by glioblastoma cells and possible function in cell invasion of three-dimensional matrices. Connect Tissue Res 31, 161–170 (1995)

    Article  CAS  PubMed  Google Scholar 

  19. P. Chen, M. Cescon, G. Zuccolotto, L. Nobbio, C. Colombelli, M. Filaferro, G. Vitale, M.L. Feltri, P. Bonaldo, Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization. Acta Neuropathol 129, 97–113 (2015). https://doi.org/10.1007/s00401-014-1369-9

    Article  PubMed  CAS  Google Scholar 

  20. M. Schnoor, P. Cullen, J. Lorkowski, K. Stolle, H. Robenek, D. Troyer, J. Rauterberg, S. Lorkowski, Production of type VI collagen by human macrophages: A new dimension in macrophage functional heterogeneity. J Immunol 180, 5707–5719 (2008)

    Article  CAS  PubMed  Google Scholar 

  21. J. Park, T.S. Morley, P.E. Scherer, Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. EMBO Mol Med 5, 935–948 (2013). https://doi.org/10.1002/emmm.201202006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. C.A. Sherman-Baust, A.T. Weeraratna, L.B.A. Rangel, E.S. Pizer, K.R. Cho, D.R. Schwartz, T. Shock, P.J. Morin, Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell 3, 377–386 (2003). https://doi.org/10.1016/s1535-6108(03)00058-8

    Article  PubMed  CAS  Google Scholar 

  23. R.R. Varma, S.M. Hector, K. Clark, W.R. Greco, L. Hawthorn, L. Pendyala, Gene expression profiling of a clonal isolate of oxaliplatin-resistant ovarian carcinoma cell line A2780/C10. Oncol Rep 14, 925–932 (2005)

    PubMed  CAS  Google Scholar 

  24. P. Iyengar, V. Espina, T.W. Williams, Y. Lin, D. Berry, L.A. Jelicks, H. Lee, K. Temple, R. Graves, J. Pollard, N. Chopra, R.G. Russell, R. Sasisekharan, B.J. Trock, M. Lippman, V.S. Calvert, E.F. Petricoin 3rd, L. Liotta, E. Dadachova, R.G. Pestell, M.P. Lisanti, P. Bonaldo, P.E. Scherer, Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115, 1163–1176 (2005). https://doi.org/10.1172/JCI23424

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. E. Tillet, B. Gential, R. Garrone, W.B. Stallcup, NG2 proteoglycan mediates beta1 integrin-independent cell adhesion and spreading on collagen VI. J Cell Biochem 86, 726–736 (2002). https://doi.org/10.1002/jcb.10268

    Article  PubMed  CAS  Google Scholar 

  26. S. Cattaruzza, P.A. Nicolosi, P. Braghetta, L. Pazzaglia, M.S. Benassi, P. Picci, K. Lacrima, D. Zanocco, E. Rizzo, W.B. Stallcup, A. Colombatti, R. Perris, NG2/CSPG4-collagen type VI interplays putatively involved in the microenvironmental control of tumour engraftment and local expansion. J Mol Cell Biol 5, 176–193 (2013). https://doi.org/10.1093/jmcb/mjt010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. M.A. Burg, E. Tillet, R. Timpl, W.B. Stallcup, Binding of the NG2 proteoglycan to type VI collagen and other extracellular matrix molecules. J Biol Chem 271, 26110–26116 (1996)

    Article  CAS  PubMed  Google Scholar 

  28. M. Chekenya, C. Krakstad, A. Svendsen, I.A. Netland, V. Staalesen, B.B. Tysnes, F. Selheim, J. Wang, P.O. Sakariassen, T. Sandal, P.E. Lonning, T. Flatmark, P.O. Enger, R. Bjerkvig, M. Sioud, W.B. Stallcup, The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. Oncogene 27, 5182–5194 (2008). https://doi.org/10.1038/onc.2008.157

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. X. Chen, Y.W. Wang, A.Y. Xing, S. Xiang, D.B. Shi, L. Liu, Y.X. Li, P. Gao, Suppression of SPIN1-mediated PI3K-Akt pathway by miR-489 increases chemosensitivity in breast cancer. J Pathol 239, 459–472 (2016). https://doi.org/10.1002/path.4743

    Article  PubMed  CAS  Google Scholar 

  30. T. Lechertier, K. Hodivala-Dilke, Focal adhesion kinase and tumour angiogenesis. J Pathol 226, 404–412 (2012). https://doi.org/10.1002/path.3018

    Article  PubMed  CAS  Google Scholar 

  31. A. Urciuolo, M. Quarta, V. Morbidoni, F. Gattazzo, S. Molon, P. Grumati, F. Montemurro, F.S. Tedesco, B. Blaauw, G. Cossu, G. Vozzi, T.A. Rando, P. Bonaldo, Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat Commun 4, 1964 (2013). https://doi.org/10.1038/ncomms2964

  32. D. Chen, P. Bhat-Nakshatri, C. Goswami, S. Badve, H. Nakshatri, ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer. Cancer Res 73, 5821–5833 (2013). https://doi.org/10.1158/0008-5472.CAN-13-1080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. A. Busch, L. Bauer, E. Wardelmann, C. Rudack, I. Grunewald, M. Stenner, Prognostic relevance of epithelial-mesenchymal transition and proliferation in surgically treated primary parotid gland cancer. J Clin Pathol 70, 403–409 (2017). https://doi.org/10.1136/jclinpath-2016-203745

    Article  PubMed  CAS  Google Scholar 

  34. A. Yemelyanova, R. Vang, M. Kshirsagar, D. Lu, M.A. Marks, M. Shih Ie, R.J. Kurman, Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: An immunohistochemical and nucleotide sequencing analysis. Mod Pathol 24, 1248–1253 (2011). https://doi.org/10.1038/modpathol.2011.85

    Article  PubMed  CAS  Google Scholar 

  35. D.G.K. Rasmussen, T.W. Hansen, B.J. von Scholten, S.H. Nielsen, H. Reinhard, H.H. Parving, M. Tepel, M.A. Karsdal, P.K. Jacobsen, F. Genovese, P. Rossing, Higher collagen VI formation is associated with all-cause mortality in patients with type 2 diabetes and microalbuminuria. Diabetes Care, dc172392 (2018). https://doi.org/10.2337/dc17-2392

    Article  PubMed  Google Scholar 

  36. J.S. Brown, U. Banerji, Maximising the potential of AKT inhibitors as anti-cancer treatments. Pharmacol Ther 172, 101–115 (2017). https://doi.org/10.1016/j.pharmthera.2016.12.001

    Article  PubMed  CAS  Google Scholar 

  37. B.Y. Lee, P. Timpson, L.G. Horvath, R.J. Daly, FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146, 132–149 (2015). https://doi.org/10.1016/j.pharmthera.2014.10.001

    Article  PubMed  CAS  Google Scholar 

  38. A. Chaudhary, M.B. Hilton, S. Seaman, D.C. Haines, S. Stevenson, P.K. Lemotte, W.R. Tschantz, X.M. Zhang, S. Saha, T. Fleming, B. St Croix, TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21, 212–226 (2012). https://doi.org/10.1016/j.ccr.2012.01.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. C. Schliemann, K.L. Gutbrodt, A. Kerkhoff, M. Pohlen, S. Wiebe, G. Silling, L. Angenendt, T. Kessler, R.M. Mesters, L. Giovannoni, M. Schafers, B. Altvater, C. Rossig, I. Grunewald, E. Wardelmann, G. Kohler, D. Neri, M. Stelljes, W.E. Berdel, Targeting interleukin-2 to the bone marrow stroma for therapy of acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation. Cancer Immunol Res 3, 547–556 (2015). https://doi.org/10.1158/2326-6066.CIR-14-0179

    Article  PubMed  CAS  Google Scholar 

  40. K.L. Gutbrodt, C. Schliemann, L. Giovannoni, K. Frey, T. Pabst, W. Klapper, W.E. Berdel, D. Neri, Antibody-based delivery of interleukin-2 to neovasculature has potent activity against acute myeloid leukemia. Sci Transl Med 5, 201ra118 (2013). https://doi.org/10.1126/scitranslmed.3006221

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was supported by the fund “Innovative Medical Research” of the University of Münster Medical School (grants SC211008 (C.S.), SC111411 (C.S.), and SC221410 (L.A. and C.S.)). W.E.B. is supported by the Deutsche Forschungsgemeinschaft (DFG EXC 1003, Cluster of excellence “Cells in Motion”).

Author information

Author notes

  1. Christoph Schliemann and Inga Grünewald share senior authorship

Authors and Affiliations

  1. Department of Medicine A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Linus Angenendt, Jan-Henrik Mikesch, Irina Arnhold, Wolfgang E. Berdel & Christoph Schliemann

  2. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

    Dennis Görlich

  3. Department of Internal Medicine II, University Hospital Eppendorf, Hamburg, Germany

    Alina Busch

  4. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Münster, Münster, Germany

    Claudia Rudack & Markus Stenner

  5. Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert Schweitzer Campus 1, 48149, Münster, Germany

    Wolfgang Hartmann, Eva Wardelmann & Inga Grünewald

Authors
  1. Linus Angenendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan-Henrik Mikesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dennis Görlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alina Busch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irina Arnhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudia Rudack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wolfgang Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eva Wardelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wolfgang E. Berdel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Markus Stenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christoph Schliemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Inga Grünewald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Linus Angenendt or Inga Grünewald.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Electronic supplementary material

ESM 1

(DOCX 290 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Angenendt, L., Mikesch, JH., Görlich, D. et al. Stromal collagen type VI associates with features of malignancy and predicts poor prognosis in salivary gland cancer. Cell Oncol. 41, 517–525 (2018). https://doi.org/10.1007/s13402-018-0389-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-018-0389-1

Keywords

Search

Navigation