Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.
The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.
Molecular and Population Genetics Laboratory, London WC2A 3PX, UK.
P J
PJ
Pollard
J J
JJ
Brière
N A
NA
Alam
J
J
Barwell
E
E
Barclay
N C
NC
Wortham
T
T
Hunt
M
M
Mitchell
S
S
Olpin
S J
SJ
Moat
I P
IP
Hargreaves
S J
SJ
Heales
Y L
YL
Chung
J R
JR
Griffiths
A
A
Dalgleish
J A
JA
McGrath
M J
MJ
Gleeson
S V
SV
Hodgson
R
R
Poulsom
P
P
Rustin
I P M
IP
Tomlinson
D002292:Carcinoma, Renal Cell / Q000378:metabolism; D002952:Citric Acid Cycle / Q000502:physiology; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics* / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase