Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer

Carmela Martini, Jessica M. Logan, Alexandra Sorvina, Colin Gordon, Andrew R. Beck, Ben S-Y. Ung, Maria C. Caruso, Courtney Moore, Ashleigh Hocking, Ian R.D. Johnson, Ka Lok Li, Litsa Karageorgos, Ashley M. Hopkins, Adrian J. Esterman, Chelsea Huzzell, Robert D. Brooks, Joanna Lazniewska, Shane M. Hickey, Christie Bader, Emma Parkinson-LawrenceRoberto Weigert, Michael J. Sorich, Prerna Tewari, Cara Martin, Sharon O'Toole, Mark Bates, Mark Ward, Bashir Mohammed, Helen Keegan, William Watson, Sophie Prendergast, Sheena Heffernan, Sarah NiMhaolcatha, Roisin O'Connor, Victoria Malone, Marguerite Carter, Katie Ryan, Nathan Brady, Andres Clarke, Filip Sokol, Sarita Prabhakaran, Jürgen Stahl, Sonja Klebe, Hemamali Samaratunga, Brett Delahunt, Stavros Selemidis, Kim L. Moretti, Lisa M. Butler, John J. O'Leary, Douglas A. Brooks

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Abstract

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology.

Original languageEnglish
Number of pages12
JournalPathology
Early online date20 Aug 2022
DOIs
Publication statusE-pub ahead of print - 20 Aug 2022

Keywords

  • Appl1
  • endosome biogenesis
  • Prostate cancer pathology
  • Sortilin
  • Syndecan-1

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