Expression of VEGF and HIF-1α in locally advanced cervical cancer: potential biomarkers for predicting preoperative radiochemotherapy sensitivity and prognosis

Abstract

Locally advanced cervical cancer (LACC) is an early-stage cervical cancer characterized by a local tumor diameter of ≥4 cm. Patients with LACC have a relatively poor prognosis. Although preoperative radiochemotherapy (PRCT) might offer a valuable opportunity for subsequent radical surgery, surgeons should also consider the nonresponsive rate, the adverse effects of PRCT, and the surgical complications before designing a treatment plan. Therefore, biomarkers for predicting PRCT sensitivity and prognosis in patients with LACC are of high importance. We investigated the prognostic significance of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) in patients with LACC. A total of 43 patients with LACC who underwent PRCT (one course each of intravenous chemotherapy and after-loading intracavitary brachytherapy followed by a radical hysterectomy) during the period 2009–2014 were included in this study. VEGF and HIF-1α expression levels were evaluated by immunohistochemistry in LACC lesions before and after PRCT. In addition, we analyzed the association of these proteins with the clinical response and pathological findings of pelvic lymph node metastasis (PLNM) after the subsequent surgery. The total clinical response rate was 81.39% after PRCT, including five complete responses and 30 partial responses. VEGF and HIF-1α expression before PRCT was significantly higher than after PRCT (VEGF: 85.71% vs 66.67%; HIF-1α: 83.33% vs 59.52%, P<0.05). In addition, the same trend was found in patients with PLNM compared to those without PLNM (VEGF: 100% vs 77.78%; HIF-1α: 100% vs 74.07%, P<0.05). The areas under the receiver operating characteristic curves were 0.896 and 0.835 when using pre-PRCT VEGF and HIF-1α expression levels, respectively, to diagnose PLNM in patients with LACC. Serial detection of VEGF and HIF-1α demonstrated a sensitivity of 66.67% and specificity of 88.89%. These findings suggest that VEGF and HIF-1α expressions are potential biomarkers for PRCT and have great clinical significance for the prediction of PRCT response and prognosis in patients with LACC.

Pulsatility Index and Hypoxia Inducible Factor-1α Expression Predict the Clinical Response after External Radiation in Patients with Stage IIB to IVA Cervical Cancer

“…The degree of tissue oxygenation have been proposed as one of the predictors of clinical response to radiation. Highly oxygenated tumor is three times more sensitive to radiation than the hypoxic or anoxic tumor (Xu et al, 2016). Tissue oxygenation and perfusion depend on 2 main factors, i.e.…”

“…We found that HIF-1α expression was significantly lower in patients with good response to radiation as compared to patients with poor response. Xu et al reported that HIF-1α expression was higher in patients with partial response as compared to patients with complete response (Xu et al, 2016). Low HIF-1α expression is associated with better response to radiation (Seeber et al, 2011).…”

“…Thus, HIF-1α is a potential biomarker to predict clinical response to radiation. Tissue hypoxia is one of the responsible mechanisms underlying the failure of radiation therapy in cervical cancer (Xu et al, 2016). Tissue hypoxia is highly associated increased HIF-1α expression.…”

“…In hypoxic condition, the effect of radiation in inhibiting transcriptional activity of HIF-1α is minimal. Hypoxia triggers increased expression of HIF-1α and production of VEGF (Xu et al, 2016). Higher HIF-1α expression will in turn increases production of proangiogenic factor.…”

“…Molecular biomarker also plays an important part as the predictor of tissue oxygenation, especially in cervical cancer. Recent studies focused on the role of Hypoxia-Inducible Factor 1α (HIF-1α) in cervical cancer (Kim et al, 2013;Huang et al, 2014;Xu et al, 2016). HIF-1α is a transcription factor that plays important part in the regulation of gene expression under hypoxic condition such as in embryogenesis, cardiovascular disease, and carcinogenesis (Sowter et al, 2003).…”