title: The identification of human pituitary adenoma-initiating cells.
abstract: Classified as benign central nervous system (CNS) tumors, pituitary adenomas account for 10% of diagnosed intracranial neoplasms. Although surgery is often curative, patients with invasive macroadenomas continue to experience significant morbidity and are prone to tumor recurrence. Given the identification of human brain tumor-initiating cells (TICs) that initiate and maintain tumor growth while promoting disease progression and relapse in multiple CNS tumors, we investigated whether TICs also drive the growth of human pituitary adenomas. Using a nanoString-based 80-gene custom codeset specific for developmental pathways, we identified a differential stem cell gene expression profile within human pituitary adenomas. Prospective functional characterization of stem cell properties in patient-derived adenomas representing all hormonal subtypes yielded a subtype-dependent self-renewal profile, which was enriched within the CD15+ cell fraction. The tumor-initiating capacity of CD15highadenoma cells was assayed in comparison to CD15lowadenomas using in vivo limiting dilutions, which maintained the rare frequency of TICs. Repeated analyses using sorted cell populations for CD15+ TICs compared to CD15- adenoma cells provided further evidence of xenograft tumor formation to support CD15+ cells as putative pituitary adenoma-initiating cells (PAICs). The clinical utility of our findings was established through in silico analyses and comparative gene expression profiling of primary and recurrent pituitary adenomas. CD15 was enriched in recurrent adenomas, which was validated using routine clinical immunohistochemistry in a limited number of samples. Our work reports the first prospective identification of human PAICs using CD15. Patients with CD15highadenomas may therefore benefit from more aggressive surgical interventions and chemo/radiotherapy.
authors.affiliation: Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada.|McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.|Departments of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Branavan
authors.initials: B
authors.lastname: Manoranjan
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.
authors.forename: Sujeivan
authors.initials: S
authors.lastname: Mahendram
authors.affiliation: Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Almenawer
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: McFarlane
authors.affiliation: Departments of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Hallett
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.
authors.forename: Thusyanth
authors.initials: T
authors.lastname: Vijayakumar
authors.affiliation: Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Almunder
authors.initials: A
authors.lastname: Algird
authors.affiliation: Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Murty
authors.affiliation: Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Doron D
authors.initials: DD
authors.lastname: Sommer
authors.affiliation: Departments of Pathology & Molecular Medicine, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: John P
authors.initials: JP
authors.lastname: Provias
authors.affiliation: Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
authors.forename: Kesava
authors.initials: K
authors.lastname: Reddy
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.|Departments of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. ssingh@mcmaster.ca.|Departments of Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. ssingh@mcmaster.ca.|Pediatric Neurosurgery, Department of Surgery, McMaster Children's Hospital, Scientist, McMaster Stem Cell & Cancer Research Institute, MDCL 5027, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016256:Lewis X Antigen / Q000378:metabolism*; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D059010:Single-Cell Analysis
chemical_list: D014408:Biomarkers, Tumor; D016256:Lewis X Antigen
keywords: Brain tumor-initiating cell; CD15; Pituitary adenoma; Pituitary adenoma stem cell; Recurrence