Cellular Oncology

, Volume 41, Issue 5, pp 517–525 | Cite as

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

  • Linus AngenendtEmail author
  • Jan-Henrik Mikesch
  • Dennis Görlich
  • Alina Busch
  • Irina Arnhold
  • Claudia Rudack
  • Wolfgang Hartmann
  • Eva Wardelmann
  • Wolfgang E. Berdel
  • Markus Stenner
  • Christoph Schliemann
  • Inga GrünewaldEmail author
Original Paper



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).


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.


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.


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.


Salivary gland carcinoma Parotid cancer Collagen type VI Tissue microarray Prognosis 



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”).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

13402_2018_389_MOESM1_ESM.docx (290 kb)
ESM 1 (DOCX 290 kb)


  1. 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)Google Scholar
  2. 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). CrossRefPubMedGoogle Scholar
  3. 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). CrossRefPubMedGoogle Scholar
  4. 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). CrossRefGoogle Scholar
  5. 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). CrossRefPubMedGoogle Scholar
  6. 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)CrossRefPubMedGoogle Scholar
  7. 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). CrossRefPubMedGoogle Scholar
  8. 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). CrossRefPubMedGoogle Scholar
  9. 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). CrossRefPubMedGoogle Scholar
  10. 10.
    M. Cescon, F. Gattazzo, P. Chen, P. Bonaldo, Collagen VI at a glance. J Cell Sci 128, 3525–3531 (2015). CrossRefPubMedGoogle Scholar
  11. 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). CrossRefPubMedGoogle Scholar
  12. 12.
    P. Chen, M. Cescon, P. Bonaldo, Collagen VI in cancer and its biological mechanisms. Trends Mol Med 19, 410–417 (2013). CrossRefPubMedGoogle Scholar
  13. 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). CrossRefPubMedGoogle Scholar
  14. 14.
    J. Park, P.E. Scherer, Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 122, 4243–4256 (2012). CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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). CrossRefPubMedGoogle Scholar
  16. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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). CrossRefPubMedGoogle Scholar
  18. 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)CrossRefPubMedGoogle Scholar
  19. 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). CrossRefPubMedGoogle Scholar
  20. 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)CrossRefPubMedGoogle Scholar
  21. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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). CrossRefPubMedGoogle Scholar
  23. 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)PubMedGoogle Scholar
  24. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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). CrossRefPubMedGoogle Scholar
  26. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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)CrossRefPubMedGoogle Scholar
  28. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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). CrossRefPubMedGoogle Scholar
  30. 30.
    T. Lechertier, K. Hodivala-Dilke, Focal adhesion kinase and tumour angiogenesis. J Pathol 226, 404–412 (2012). CrossRefPubMedGoogle Scholar
  31. 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).
  32. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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). CrossRefPubMedGoogle Scholar
  34. 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). CrossRefPubMedGoogle Scholar
  35. 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). CrossRefPubMedGoogle Scholar
  36. 36.
    J.S. Brown, U. Banerji, Maximising the potential of AKT inhibitors as anti-cancer treatments. Pharmacol Ther 172, 101–115 (2017). CrossRefPubMedGoogle Scholar
  37. 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). CrossRefPubMedGoogle Scholar
  38. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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). CrossRefPubMedGoogle Scholar
  40. 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). CrossRefPubMedGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2018

Authors and Affiliations

  • Linus Angenendt
    • 1
    Email author
  • Jan-Henrik Mikesch
    • 1
  • Dennis Görlich
    • 2
  • Alina Busch
    • 3
  • Irina Arnhold
    • 1
  • Claudia Rudack
    • 4
  • Wolfgang Hartmann
    • 5
  • Eva Wardelmann
    • 5
  • Wolfgang E. Berdel
    • 1
  • Markus Stenner
    • 4
  • Christoph Schliemann
    • 1
  • Inga Grünewald
    • 5
    Email author
  1. 1.Department of Medicine AUniversity Hospital MünsterMünsterGermany
  2. 2.Institute of Biostatistics and Clinical ResearchUniversity of MünsterMünsterGermany
  3. 3.Department of Internal Medicine IIUniversity Hospital EppendorfHamburgGermany
  4. 4.Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital of MünsterMünsterGermany
  5. 5.Gerhard-Domagk-Institute of PathologyUniversity Hospital MünsterMünsterGermany

Personalised recommendations