title: Co-expression of TTF-1 and neuroendocrine markers in the human fetal lung and pulmonary neuroendocrine tumors.
abstract: The expression pattern of thyroid transcription factor 1 (TTF-1) and neuroendocrine markers, neuron cell adhesion molecule (NCAM; CD56), chromogranin A (CgA) and synaptophysin (Syp), of different lung cell lineages was histologically analyzed in 15 normal human fetal lungs and 12 neuroendocrine tumors (NETs) using immunohistochemical methods. During pseudoglandular phase strong nuclear TTF-1 staining was detected in the columnar nonciliated epithelial cells, while NCAM, CgA and Syp had a moderate expression in the proximal airways and mild expression in the distal airways. Neuroendocrine cells (NECs) in proximal lung airway were co-localizing TTF-1 and other neuroendocrine markers while neuroendocrine bodies (NEBs) exhibit only staining with NCAM and Syp. In the canalicular phase TTF-1 nuclear staining was expressed only in several epithelial cells in proximal airways, while budding airways epithelium showed strong TTF-1 expression. Expression of NCAM, CgA and Syp in this phase equals the one in pseudoglandular phase. NEBs cells were co-localizing TTF-1 and NCAM in proximal airways and few NECs in distal airway were co-localizing TTF-1 and Syp. TTF-1 staining in the saccular phase was limited to subsets of epithelial cells in the proximal airways with stronger positivity in the distal airways. NCAM expression is moderate only in proximal airways, while Syp and CgA show mild expression in proximal and distal airways. NECs were co-localizing TTF-1 and NCAM in proximal lung airway. With regard to NECs, all small cell lung cancer (SCLC) cells had strong TTF-1, NCAM, Syp and CgA positivity and TTF-1 co-localized with other neuroendocrine markers. All pulmonary typical carcinoids were TTF-1 negative, while pulmonary atypical carcinoids were focal positive for TTF-1 and some neoplastic cells co-localized TTF-1 with neuroendocrine markers. Our results indicate that TTF-1 expression in NECs suggests a possible role in their normal development and differentiation. Our results also indicate that possible cell of origin for poorly differentiated SCLC and some atypical carcinoid could be a progenitor cell in neuroendocrine lineage while in typical carcinoids possible cell of origin is localized in terminally differentiated NECs.
authors.affiliation: Department of Surgery, University Hospital in Mostar, KraljaTvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
authors.forename: Josip
authors.initials: J
authors.lastname: Miskovic
authors.affiliation: Department of Surgery, University Hospital in Mostar, KraljaTvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
authors.forename: Zdrinko
authors.initials: Z
authors.lastname: Brekalo
authors.affiliation: Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Vukojevic
authors.affiliation: Department of Neonatology, University Hospital in Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
authors.forename: Helena Radic
authors.initials: HR
authors.lastname: Miskovic
authors.affiliation: Department of Pediatrics, University Hospital in Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kraljevic
authors.affiliation: Department of Pathology, Cytology and Forensic Medicine, University Hospital in Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
authors.forename: Jelena
authors.initials: J
authors.lastname: Todorovic
authors.affiliation: Department of Pathology, Cytology and Forensic Medicine, University Hospital in Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; Department of Histology and Embryology, School of Medicine, University of Mostar, Bijeli brijeg bb, 88000 Mostar, Bosnia and Herzegovina. Electronic address: vsoljic@gmail.com.
authors.forename: Violeta
authors.initials: V
authors.lastname: Soljic
mesh_terms: D000943:Antigens, Differentiation / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000196:embryology* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors
chemical_list: D000943:Antigens, Differentiation; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors
keywords: Fetal lung; Markers; Neuroendocrine cell; TTF-1; Tumors