Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome

Patrick Pollard, Noel Wortham, Ella Barclay, Afrina Alam, George Elia, Sanjiv Manek, Richard Poulsom, Ian Tomlinson

Research output: Contribution to journalArticlepeer-review

Abstract

The Mendelian tumour syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis with phaeochromocytomas (HPGL) result from mutations in nuclear genes (FH and SDHB/C/D, respectively) that encode Krebs cycle enzymes. HPGL tumours are highly vascular and there is evidence that inactivation of SDH leads to activation of the hypoxia/angiogenesis pathway. In contrast, uterine leiomyomas are not generally regarded as particularly vascular lesions. In order to test the possibility that activation of the hypoxia/angiogenesis pathway contributes to tumourigenesis in HLRCC, increased vascularity and hypoxia pathway activation were searched for in HLRCC tumours. Microvessel density was markedly higher in uterine leiomyomas from HLRCC than in the surrounding myometrium; it was notable that sporadic uterine leiomyomas were actually less vascular than normal myometrium. In HLRCC tumours, there was increased expression of transcripts from the hypoxia-responsive genes vascular endothelial growth factor (VEGF) and BNIP3; sporadic uterine leiomyomas did not show these changes. All uterine leiomyomas showed decreased expression of thrombospondin 1. Although sporadic and HLRCC uterine leiomyomas appear to have identical morphology, their pathways of tumourigenesis may be fundamentally different. As is the case in HPGL, it is probable that failure of the Krebs cycle in HLRCC tumours causes inappropriate signalling that the cell is in a hypoxic state, leading to angiogenesis and perhaps directly to clonal expansion and tumour growth through some uncharacterized, cell-autonomous effect.
Original languageEnglish
Pages (from-to)41-9
Number of pages9
JournalThe Journal of Pathology
Volume205
Issue number1
DOIs
Publication statusPublished - Jan 2005

Keywords

  • Adult
  • Carcinoma, Renal Cell
  • Cell Hypoxia
  • Female
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization
  • Kidney Neoplasms
  • Leiomyomatosis
  • Neoplastic Syndromes, Hereditary
  • Neovascularization, Pathologic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin Neoplasms
  • Uterine Neoplasms

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