Novel predictive biomarkers for cervical cancer prognosis

Abstract

Abstract. High hypoxic, glycolytic and acidosis metabolisms characterize cervical cancer tumors and have been described to be involved in chemoradioresistance mechanisms. Based on these observations, the present study assessed four selected novel biomarkers on the prognosis of locally advanced cervical carcinoma. A total of 66 patients with stage IIB/IIIB cervical cancer were retrospectively included. The protein expression levels of glucose transporter 1 (GLUT1), carbonic anhydrase 9 (CAIX) and hexokinase 1 (HKII) were investigated by immunohistochemistry on tumor biopsies, hemoglobin was measured and the disease outcome was monitored. A total of 53 patients (80.3%) presented a complete response. For these patients, the protein expression levels of GLUT1, CAIX and HKII were overexpressed. A significant difference was observed (P= 0.0127) for hemoglobin levels (≤11 g/dl) in responsive compared with non-responsive patients. The expression of GLUT1 is associated with a lower rate of both overall and disease-free survival, with a trend of decreased risk of 1.1x and 1.5x, respectively. Co-expression of GLUT1 and HKII is associated with a decreased trend risk of 1.6x for overall survival. Patients with hemoglobin levels ≤11 g/dl had a 4.3-fold risk (P=0.02) in decreasing both to the rate of overall and disease-free survival. The presence of anemic hypoxia (hemoglobin ≤11 g/dl) and the expression of GLUT1 and/or HKII influence treatment response and are associated with a lower overall and disease-free survival. The present results demonstrated that these biomarkers may be used as predictive markers and suggested that these metabolic pathways can be used as potential novel therapeutic targets.

Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma

“…A survival benefit of 12% was previously reported with the combination of chemotherapy + radiotherapy in CC patients [20]. The present findings clearly confirm that patients with locally advanced CC should undergo concomitant chemoradiation, in accordance with international guidelines.…”

“…However in our set of patients, no significant correlation was identified between hemoglobin level and Karnofsky index, suggesting that the poor prognosis value of anemia could not only been seen through the prism of the performance status. Furthermore, previous experimental and clinical studies suggested a direct association between anemia and a poor tumor oxygenation [20], limiting the radio-induced oxygen effect and therefore decreasing the efficacy of radiotherapy. In squamous cell carcinoma and especially in CC, the prognostic impact of anemia is well-established [3, 7, 20].…”

“…Furthermore, previous experimental and clinical studies suggested a direct association between anemia and a poor tumor oxygenation [20], limiting the radio-induced oxygen effect and therefore decreasing the efficacy of radiotherapy. In squamous cell carcinoma and especially in CC, the prognostic impact of anemia is well-established [3, 7, 20]. Our findings suggest that besides molecular biomarkers, hemoglobin could a reliable, inexpensive and easily accessible biomarker of radiation-resistance.…”

“…Interestingly, HKII was shown to protect cells against oxidative stress, the main mechanism of radio-induced DNA damage and death. Moreover, the value of GLUT-1, HKII and GAPDH (another glycolysis-related factor) as endogenous marker of hypoxia was proven, with a correlation between increased expressions of proteins and tissue hypoxia [3, 7, 18, 20]. The overexpression of HIF-1 alpha, a protein induced by hypoxia that upregulates pro-survival and pro-proliferation signaling pathways, was reported to be a predictive marker of response and prognosis in locally advanced CCs treated with exclusive radiotherapy [21].…”

GLUT1 expression in human papillomavirus‐positive anogenital lesions

“…This overexpression is assumed to provide the increased need of glucose for aerobic glycolysis in cancer cells (Warburg effect), in order to sustain proliferation. Induction of GLUT1 mRNA and protein has been considered as an early event in cervical neoplasia as well as in other oncogenic virus‐mediated cellular transformation . In head and neck carcinoma, human papillomavirus (HPV)‐positive cancers display a higher GLUT1 expression, associated with a lower tumour hypoxia signature .…”