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

Serrated colorectal adenocarcinoma (SAC) is a morphologically distinct subtype of colorectal cancer (CRC), in which increased HIF-1 alpha mRNA expression and HIF-1 alpha protein stabilization are typical features. Here we aimed to further elucidate HIF-1 alpha 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-1 alpha 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-1 alpha and VEGF were expressed in the vast majority of SPs and NSAs. In CRCs, HIF-1 alpha protein was also present in 77.8 % of SACs, while only 20.3 % of CCs were HIF-1 alpha proficient. MVD was significantly higher in SACs, but the serrated morphology was the only significant predictor of MVD in CRC in multivariate analyses. HIF-1 alpha protein is often stabilized in well-vascularized SACs, suggesting hypoxia-independent stabilization of HIF-1 alpha. Moreover, HIF-1 alpha stabilization did not associate with oncogenic activation of BRAF or KRAS or Von Hippel-Lindau (VHL) mutation. Prevalent HIF-1 alpha expression in SAC and its precursors support the importance of HIF-1 alpha-mediated pathways for the serrated route of colorectal carcinogenesis.