title: Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma.
abstract: BACKGROUND
  An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far.
  
  
  METHODS
  Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model.
  
  
  RESULTS
  Immunohistochemical analysis showed an improved prognosis of ALDH1A2(high) OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2(high)CRABP2(high) staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression.
  
  
  CONCLUSIONS
  This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2(low) tumors might benefit from adjuvant treatment with retinoids.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. k.seidensaal@yahoo.de.|Research Group Molecular Mechanisms of Head and Neck Tumor, German Cancer Research Center (DKFZ), Heidelberg, Germany. k.seidensaal@yahoo.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Seidensaal
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. andre.nollert@gmx.de.
authors.forename: Andre
authors.initials: A
authors.lastname: Nollert
authors.affiliation: Service d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université Lausanne, Lausanne, Switzerland. agnes.hiou@chuv.ch.
authors.forename: Agnes Hiou
authors.initials: AH
authors.lastname: Feige
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. marief4@web.de.
authors.forename: Marie
authors.initials: M
authors.lastname: Muller
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany. thomas.fleming@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.affiliation: Cancer Drug Discovery, German Cancer Research Center Heidelberg, Heidelberg, Germany. n.gunkel@dkfz-heidelberg.de.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Gunkel
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. karim.zaoui@med.uni-heidelberg.de.
authors.forename: Karim
authors.initials: K
authors.lastname: Zaoui
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany. niels.grabe@bioquant.uni-heidelberg.de.|Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. niels.grabe@bioquant.uni-heidelberg.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. wilko.weichert@tum.de.|National Center for Tumor Diseases (NCT), Heidelberg, Germany. wilko.weichert@tum.de.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany. wilko.weichert@tum.de.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany. klaus-josef.weber@med.uni-heidelberg.de.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. peter.plinkert@med.uni-heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Plinkert
authors.affiliation: Service d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université Lausanne, Lausanne, Switzerland. Christian.Simon@chuv.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Simon
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Section Experimental and Translational Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany. Jochen.Hess@med.uni-heidelberg.de.|Research Group Molecular Mechanisms of Head and Neck Tumor, German Cancer Research Center (DKFZ), Heidelberg, Germany. Jochen.Hess@med.uni-heidelberg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase