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

Virchows Arch. 2016 Oct;469(4):395-404. doi: 10.1007/s00428-016-1988-8. Epub 2016 Jul 15.


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.

Keywords: Colorectal cancer; HIF-1; Microvessel density; Serrated adenocarcinoma.

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / pathology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms / blood supply
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Male
  • Microvessels / pathology*
  • Middle Aged
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology*
  • Vascular Endothelial Growth Factor A / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A