Re-expression of pro-fibrotic, embryonic preserved mediators in irradiated arterial vessels of the head and neck region

Reexpression profibrotischer, embryonal konservierter Mediatoren in bestrahlten arteriellen Gefäßen der Kopf- und Halsregion



Surgical treatment of head and neck malignancies frequently includes microvascular free tissue transfer. Preoperative radiotherapy increases postoperative fibrosis-related complications up to transplant loss. Fibrogenesis is associated with re-expression of embryonic preserved tissue developmental mediators: osteopontin (OPN), regulated by sex-determining region Y‑box 9 (Sox9), and homeobox A9 (HoxA9) play important roles in pathologic tissue remodeling and are upregulated in atherosclerotic vascular lesions; dickkopf-1 (DKK1) inhibits pro-fibrotic and atherogenic Wnt signaling. We evaluated the influence of irradiation on expression of these mediators in arteries of the head and neck region.

Materials and methods

DKK1, HoxA9, OPN, and Sox9 expression was examined immunohistochemically in 24 irradiated and 24 nonirradiated arteries of the lower head and neck region. The ratio of positive cells to total cell number (labeling index) in the investigated vessel walls was assessed semiquantitatively.


DKK1 expression was significantly decreased, whereas HoxA9, OPN, and Sox9 expression were significantly increased in irradiated compared to nonirradiated arterial vessels.


Preoperative radiotherapy induces re-expression of embryonic preserved mediators in arterial vessels and may thus contribute to enhanced activation of pro-fibrotic downstream signaling leading to media hypertrophy and intima degeneration comparable to fibrotic development steps in atherosclerosis. These histopathological changes may be promoted by HoxA9-, OPN-, and Sox9-related inflammation and vascular remodeling, supported by downregulation of anti-fibrotic DKK1. Future pharmaceutical strategies targeting these vessel alterations, e. g., bisphosphonates, might reduce postoperative complications in free tissue transfer.



Die operative Behandlung von Tumoren im Kopf- und Halsbereich umfasst den Transfer mikrovaskulärer Gewebetransplantate. Präoperative Bestrahlung verursacht eine erhöhte Inzidenz fibrosebedingter Komplikationen bis zum Transplantatverlust. Die Fibroseentstehung ist mit der Reexpression embryonal konservierter, in der Gewebeentwicklung relevanter Mediatoren assoziiert: Osteopontin (OPN), reguliert von Sex determining region Y‑box 9 (Sox9), und Homeobox A9 (HoxA9) spielen wichtige Rollen im pathologischen Gewebeumbau und sind hochreguliert in arteriosklerotischen Gefäßläsionen; Dickkopf-1 (DKK1) inhibiert den profibrotischen, atherogenen Wnt-Signalweg. Wir untersuchten den Einfluss der Bestrahlung auf die Expression dieser Mediatoren in Arterien der Kopf- und Halsregion.

Material und Methoden

Die Expression von DKK1, HoxA9, OPN und Sox9 wurde in 24 bestrahlten und 24 nichtbestrahlten Arterien der unteren Kopf- und Halsregion immunhistochemisch untersucht. Das Verhältnis positiver Zellen zur Gesamtzellzahl (Färbungsindex) in den untersuchten Gefäßwänden wurde semiquantitativ bestimmt.


Die Expression von DKK1 war in bestrahlten im Vergleich zu nichtbestrahlten arteriellen Gefäßen signifikant erniedrigt, die von HoxA9, OPN und Sox9 hingegen signifikant erhöht.


Präoperative Bestrahlung induziert die Reexpression embryonal konservierter Mediatoren in arteriellen Gefäßen und könnte somit zur verstärkten Aktivierung des profibrotischen Downstreams beitragen, was zu Mediahypertrophie und Intimadegeneration, vergleichbar mit fibrotischen Entwicklungsstufen bei Arteriosklerose, führt. Diese histopathologischen Veränderungen könnten durch HoxA9-, OPN- und Sox9-beeinflusste Inflammation und Gefäßumbau begünstigt werden, unterstützt durch die Herabregulierung des antifibrotischen DKK1. Pharmazeutische Strategien gegen derartige Gefäßveränderungen, z. B. mit Bisphosphonaten, könnten postoperative Komplikationen nach freiem Gewebetransfer reduzieren.

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The present study was financially supported by the “ELAN Fonds der Universität Erlangen”.

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Correspondence to Patrick Möbius.

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P. Möbius, R.H.M. Preidl, M. Weber, K. Amann, F.W. Neukam, and F. Wehrhan declare that they have no competing interests.

Ethical standards

All studies on humans presented in this manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Ethical aspects of the present study are approved by the ethics committee of the University of Erlangen-Nuremberg, Germany (Ref.-No. 83_13B).

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Author Contribution

P. Möbius, R.H.M. Preidl, and F. Wehrhan designed the study. P. Möbius, R.H.M. Preidl, and M. Weber collected the data. P. Möbius wrote the manuscript. F. Wehrhan formulated the hypothesis and contributed to the manuscript. M. Weber critically reviewed the article and contributed to the discussion. K. Amann helped validating the markers and contributed to the discussion. F.W. Neukam contributed to the discussion and critically reviewed the article. All authors approved the final version.

Shared first authors: P. Möbius and R.H.M. Preidl.

The present work was performed in (partial) fulfillment of the requirements for obtaining the degree “Dr. med.” (P. Möbius).

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Möbius, P., Preidl, R.H.M., Weber, M. et al. Re-expression of pro-fibrotic, embryonic preserved mediators in irradiated arterial vessels of the head and neck region. Strahlenther Onkol 193, 951–960 (2017).

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  • Radiotherapy
  • Vascular remodeling
  • Embryology
  • Immunohistochemistry
  • Inflammation


  • Strahlentherapie
  • Gefäßumbau
  • Immunhistochemie
  • Embryologie
  • Entzündung