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HIF-1α expression and high microvessel density are characteristic features in serrated colorectal cancer

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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.

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Abbreviations

CC:

Conventional carcinoma

CRC:

Colorectal cancer

HIF:

Hypoxia-inducible transcription factor

HP:

Hyperplastic polyp

MVD:

Microvessel density

NSA:

Non-serrated adenoma

SP:

Serrated polyp

SAC:

Serrated adenocarcinoma

TSA:

Traditional serrated adenoma

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Acknowledgments

We are grateful to Fundación para la Formación e Investigación Sanitarias from Healthcare Council of Murcia Region, Spain. We are grateful to Prof. Tuomo Karttunen for the fruitful discussions and critical reading of the manuscript.

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Authors and Affiliations

  1. Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, POB 5000, 90014, Oulu, Finland

    Anne Tuomisto, Päivi Sirniö, Juha Väyrynen & Markus J Mäkinen

  2. Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland

    Anne Tuomisto, Päivi Sirniö, Juha Väyrynen & Markus J Mäkinen

  3. Department of Pathology, Santa Lucía University Hospital, C/Mezquita sn, 30202, Cartagena, Spain

    José García-Solano, Miguel Pérez-Guillermo & Pablo Conesa-Zamora

  4. Facultad de Ciencias de la Salud, Catholic University of Murcia (UCAM), Murcia, Spain

    José García-Solano & Pablo Conesa-Zamora

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  1. Anne Tuomisto
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Corresponding authors

Correspondence to Anne Tuomisto or Pablo Conesa-Zamora.

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Sources of funding

This work was supported by two grants from Instituto de Salud Carlos III, Ministerio de Sanidad, Spain (references PI08–1210 and PI12–1232) and grants from Academy of Finland (24,300,234), Emil Aaltonen Foundation, Finnish Cancer Foundation, and Northern Finland Cancer Foundation.

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The authors declare that they have no conflict of interest.

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Anne Tuomisto and José García-Solano contributed equally to this work

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Tuomisto, A., García-Solano, J., Sirniö, P. et al. HIF-1α expression and high microvessel density are characteristic features in serrated colorectal cancer. Virchows Arch 469, 395–404 (2016). https://doi.org/10.1007/s00428-016-1988-8

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  • DOI: https://doi.org/10.1007/s00428-016-1988-8

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