The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer.
Vascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue microarray of clinical samples (N=86), tumour cell immunohistochemical staining of AKT/mTOR downstream targets, pS6 and p4E-BP1, together with tumour cell staining of VEGF-A and pVEGFR2 were semi-quantified. A correlation was found between the marker for VEGFR2 activation (pVEGFR2) and a downstream target of AKT/mTOR signalling (pS6) (R=0.29; P=0.002). Additional gene expression analysis in an independent cDNA microarray dataset (N=24) showed a negative correlation (R=-0.73, P<0.0001) between the RPS6 and the VEGFR2 gene, which is consistent as the gene expression and phosphorylation of S6 is inversely regulated. An activated tumour cell VEGFR2/AKT/mTOR pathway was associated with increased incidence of ascites (chi(2), P=0.002) and reduced overall survival of cisplatin-taxane-based patients with serous histology (N=32, log-rank test, P=0.04). These data propose that VEGF-A signalling acts on tumour cells as a stimulator of the AKT/mTOR pathway. Although VEGF-A inhibitors are classified as anti-angiogenic drugs, these data suggest that the working mechanism has an important additional modality of targeting the tumour cells directly.
Trinh
X B
XB
Translational Cancer Research Group Antwerp, St Augustinus Hospital, Antwerp, Belgium.
Tjalma
W A A
WA
Vermeulen
P B
PB
Van den Eynden
G
G
Van der Auwera
I
I
Van Laere
S J
SJ
Helleman
J
J
Berns
E M J J
EM
Dirix
L Y
LY
van Dam
P A
PA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology
D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases