Hypoxia, angiogenesis and apoptosis markers in locally advanced rectal cancer.
OBJECTIVE
Hypoxia-inducible factor 1alpha (HIF-1alpha) is a critical regulatory protein of cellular response to hypoxia. HIF-1alpha triggers the angiogenic process through activation of the vascular endothelial factor (VEGF) gene. The bcl-2 anti-apoptotic and the death promoting p53 genes, regulate the apoptotic cell death. We investigated the relationship between hypoxia, angiogenesis and apoptosis and their prognostic impact in patients with advanced rectal cancer.


METHODS
The immunohistochemical expression of HIF-1alpha, VEGF, p53 and bcl-2 and the determination of microvessel density (MVD), apoptotic index (AI) were carried out in tumour tissue samples obtained from 92 patients with locally advanced rectal cancer (LARC) (T3,4/N+/-).


RESULTS
HIF-1alpha high reactivity and VEGF overexpression were noted in 47.8 and 44.6% of the examined cases, respectively. They significantly correlated with lymph node metastasis (P<0.001) and low rectal location (P=0.016). HIF-1alpha expression was directly correlated with VEGF up-regulation (P<0.001) and MVD (P<0.001). VEGF expression was closely interrelated with MVD (P<0.001). In univariate analysis advanced grade, infiltrative pattern of tumour growth, vascular invasion, positive lymph node status, HIF-1alpha expression and VEGF upregulation were related to decreased disease-free and overall survival. In multivariate analysis, only high HIF-1alpha reactivity and positive lymph node status emerged as independent variables of adverse prognostic significance.


CONCLUSIONS
HIF-1alpha and VEGF may play an important predictive and prognostic role in patients with LARC.
Theodoropoulos
George E
GE
1st Propaideutic Surgical Department, Hippocration University Hospital, Athens, Greece.
Lazaris
Andreas C
AC
Theodoropoulos
Vasilios E
VE
Papatheodosiou
Kalliopi
K
Gazouli
Maria
M
Bramis
John
J
Patsouris
Efstratios
E
Panoussopoulos
Dimitrios
D
D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D012004:Rectal Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery; D012008:Recurrence; D012189:Retrospective Studies
D014408:Biomarkers, Tumor