title: HIF-1α expression and high microvessel density are characteristic features in serrated colorectal cancer.
abstract: Serrated colorectal adenocarcinoma (SAC) is a morphologically distinct subtype of colorectal cancer (CRC), in which increased HIF-1α mRNA expression and HIF-1α protein stabilization are typical features. Here we aimed to further elucidate HIF-1α protein expression in serrated and non-serrated colorectal carcinomas (CRCs) and their precursor lesions and its association with vascular endothelial growth factor (VEGF) and microvascular density (MVD). HIF-1α and VEGF expressions were determined immunohistochemically in 134 serrated polyps (SPs), 104 non-serrated adenomas (NSAs), 81 SACs, and 74 matched conventional adenocarcinomas (CCs) and were correlated with morphology, clinicopathological features, and MVD. In premalignant lesions, both HIF-1α and VEGF were expressed in the vast majority of SPs and NSAs. In CRCs, HIF-1α protein was also present in 77.8 % of SACs, while only 20.3 % of CCs were HIF-1α proficient. MVD was significantly higher in SACs, but the serrated morphology was the only significant predictor of MVD in CRC in multivariate analyses. HIF-1α protein is often stabilized in well-vascularized SACs, suggesting hypoxia-independent stabilization of HIF-1α. Moreover, HIF-1α stabilization did not associate with oncogenic activation of BRAF or KRAS or Von Hippel-Lindau (VHL) mutation. Prevalent HIF-1α expression in SAC and its precursors support the importance of HIF-1α-mediated pathways for the serrated route of colorectal carcinogenesis.
authors.affiliation: Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, POB 5000, 90014, Oulu, Finland. anne.tuomisto@oulu.fi.|Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland. anne.tuomisto@oulu.fi.
authors.forename: Anne
authors.initials: A
authors.lastname: Tuomisto
authors.affiliation: Department of Pathology, Santa Lucía University Hospital, C/Mezquita sn, 30202, Cartagena, Spain.|Facultad de Ciencias de la Salud, Catholic University of Murcia (UCAM), Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: García-Solano
authors.affiliation: Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, POB 5000, 90014, Oulu, Finland.|Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Sirniö
authors.affiliation: Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, POB 5000, 90014, Oulu, Finland.|Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Väyrynen
authors.affiliation: Department of Pathology, Santa Lucía University Hospital, C/Mezquita sn, 30202, Cartagena, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pérez-Guillermo
authors.affiliation: Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, POB 5000, 90014, Oulu, Finland.|Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Mäkinen
authors.affiliation: Department of Pathology, Santa Lucía University Hospital, C/Mezquita sn, 30202, Cartagena, Spain. Pablo.conesa@carm.es.|Facultad de Ciencias de la Salud, Catholic University of Murcia (UCAM), Murcia, Spain. Pablo.conesa@carm.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Conesa-Zamora
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A
keywords: Colorectal cancer; HIF-1; Microvessel density; Serrated adenocarcinoma