Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha.
BACKGROUND
Hepatocellular carcinoma (HCC) is a hypervascular tumor and angiogenesis plays an important role in its progression. Angiogenesis is regulated by a balance between pro and antiangiogenic molecules. The aim of this study was to investigate the expressions of angiogenic factors and elucidate their roles in angiogenesis in HCC.


METHODS
We investigated immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), hypoxia-induced factor-1alpha (HIF-1alpha) and thrombospondin-1 (TSP-1) in 60 specimens of surgically resected HCC. We investigated the relationship between their expressions and clinicopathological factors or prognosis.


RESULTS
Ang-2 staining had a significant correlation with the grade of differentiation of HCC cells (P=0.0082). VEGF and Ang-2 expression correlated positively with microvessel density (MVD) (P=0.0061 and 0.0374, respectively). MVD of well-differentiated HCC were significantly lower than those of moderately and poorly differentiated HCC. The disease-free survival time of patients with high Ang-2 and/or HIF-1alpha expression was significantly shorter than that of the low expression group (P=0.0278 and 0.0374, respectively).


CONCLUSIONS
Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.
Wada
Hiroshi
H
Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Nagano
Hiroaki
H
Yamamoto
Hirofumi
H
Yang
Yubo
Y
Kondo
Motoi
M
Ota
Hideo
H
Nakamura
Masato
M
Yoshioka
Shinichi
S
Kato
Hitoshi
H
Damdinsuren
Bazarragchaa
B
Tang
Di
D
Marubashi
Sigeru
S
Miyamoto
Atsushi
A
Takeda
Yutaka
Y
Umeshita
Koji
K
Nakamori
Shoji
S
Sakon
Masato
M
Dono
Keizo
K
Wakasa
Kenichi
K
Monden
Morito
M
D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C467630:ANGPT1 protein, human; D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A