Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) in esophageal squamous cell carcinoma.
BACKGROUND
To clarify the clinical significance of vascular endothelial growth factor (VEGF) and its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1), in esophageal cancers, we evaluated the relationships between the expression of VEGF and its receptors, tumor microvessel density (MVD), clinicopathological factors and prognosis.


METHODS
Thoracic esophageal squamous cell carcinoma (SCC) specimens were obtained during surgery from 64 previously untreated patients. Expression levels of VEGF and its receptors were determined immunohistochemically, and tumor MVD was assessed.


RESULTS
Twenty-four (37.5%) of the tumors showed diffuse VEGF immunoreactivity. VEGF expression was significantly correlated with tumor status (p < 0.05) and poor prognosis (log-rank; p < 0.05). VEGFR-1 immunoreactivity was detected in the cytoplasm of the cancer cells in 27 patients (42.2%). VEGFR-1-positive cancers tended to be associated with poorer nodal status (p = 0.1513), but VEGFR-1 expression did not correlate with prognosis in the univariate survival analysis (p = 0.2964). VEGFR-2 immunoreactivity was detected in the cancer cell cytoplasm in 26 patients (40.6%), but VEGFR-2 expression did not correlate with clinicopathological factors or prognosis. Comparison of the MVD and clinicopathological characteristics revealed significant associations between high MVD and poorer tumor status (p < 0.05), blood vessel invasion (p < 0.05) and poor prognosis (p < 0.01). In the multivariate analysis, MVD was identified as an independent prognostic factor as well as depth of tumor invasion and lymph node metastasis. Although VEGF expression correlated significantly with the MVD (p < 0.05), the correlations between VEGFR-1 and VEGFR-2 expression and the MVD were not significant. There were, however, significant intercorrelations in expression between VEGF, VEGFR-1 and VEGFR-2.


CONCLUSIONS
Vascular endothelial growth factor (VEGF) may play a role in the control of angiogenesis in esophageal squamous cell carcinoma. However, although VEGF expression correlates significantly with coexpression of its receptors, VEGFR-1 and VEGFR-2, these receptors do not appear to contribute directly to tumor progression. Nevertheless, VEGF and its receptors represent a logical target for antiangiogenic therapy for esophageal SCC.
Kato
Hiroyuki
H
Department of Surgery I, Gunma University Faculty of Medicine, Maebashi, 371-8511, Japan. hiroyuki@po.wind.ne.jp
Yoshikawa
Minako
M
Miyazaki
Tatsuya
T
Nakajima
Masanobu
M
Fukai
Yasuyuki
Y
Masuda
Norihiro
N
Fukuchi
Minoru
M
Manda
Ryokuhei
R
Tsukada
Katsuhiko
K
Kuwano
Hiroyuki
H
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008222:Lymphokines / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2