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.
ABSTRACT
Objetivo. Determinar la expresión de CAIX, GLUT-1, HKII y establecer si existe asociación entre la expresión y la respuesta temprana al tratamiento en carcinomas escamocelulares de cuello uterino. Sujetos y métodos. En este estudio de tipo cohorte retrospectiva se incluyó a 66 pacientes en estadios FIGO IIB y IIIB durante el periodo del 2001 al 2007, con una edad promedio de 47 años. De las 66 pacientes, 22 fueron tratadas con radioterapia exclusiva y 44 con quimioterapia concomitante a radioterapia. La expresión de las proteínas CAIX, GLUT-1 y HKII fue determinada mediante inmunohistoquímica en biopsias tomadas antes del tratamiento. Resultados. Se encontró un mayor incremento en la expresión de GLUT-1 (74%), seguido de CAIX (41%) y HKII (18%). La coexpresión de GLUT-1 y CAIX resultó ser significativa (p < 0,002) en comparación con GLUT-1 y HKII. Además, se observó una tendencia de riesgo de no respuesta cuando se expresan simultáneamente las 3 proteínas. Conclusiones. El incremento en la expresión de GLUT-1 respecto de CAIX y HKII reafirma el concepto de que los carcinomas tienen un alto consumo de glucosa y su coexpresión con CAIX y HKII como factores biológicos preexistentes puede contribuir a esclarecer los mecanismos de hipoxia en la invasión tumoral, así como su posible efecto frente a tratamientos como la radioterapia exclusiva y la radioquimioterapia concomitante para el manejo de cáncer de cuello uterino en estadios ii B y iii B (AU)
Objective: To determine the expression of CAIX, GLUT-1 and HKII and whether there is an association between expression of these markers and early treatment response in squamous cell carcinomas of the uterine cervix. Subjects and methods: This retrospective cohort study included 66 patients with squamous cell carcinomas of the uterine cervix in FIGO (International Federation of Gynecology and Obstetrics) stages IIB and IIIB between 2001 and 2007. The mean age was 47 years. Of the 66 patients, 22 were treated with radiotherapy and 44 with concurrent radiochemotherapy. Expression of the proteins CAIX, GLUT-1 and HKII was determined by immunohistochemistry in biopsies taken before treatment. Results: The highest increase was found in expression of GLUT-1 (74%), followed by that of CAIX (41%) and HKII (18%). Coexpression of GLUT-1 and CAIX was significant (p <0.002) compared with that of GLUT-1 and HKII. When all three proteins were expressed simultaneously, we observed a tendency toward lack of treatment response. Conclusions: Increased expression of GLUT-1 compared with that of CAIX and HKII supports the notion that carcinomas have high glucose consumption. Coexpression of GLUT-1 with CAIX and HKII as preexisting biological factors could help to elucidate the mechanisms of hypoxia in tumoral invasion. Coexpression could also help to explain the possible effect of these markers on response to treatments such as exclusive radiotherapy and concurrent radiochemotherapy in the management of stage IIB and IIIB cervical cancer (AU)
Subject(s)
Humans , Female , Biomarkers/analysis , Uterine Cervical Neoplasms/diagnosis , Cervix Uteri/cytology , Cervix Uteri , Cervix Uteri/pathology , Immunohistochemistry/methods , Immunohistochemistry/standards , Immunohistochemistry , Sodium-Glucose Transporter 1 , Carcinoma/diagnosis , Immunohistochemistry/instrumentation , Carbonic Anhydrase Inhibitors , Carbonic Anhydrases , Hexokinase , Glycolysis , Glycolysis/physiologyABSTRACT
AIM: The aim of this study was to evaluate the predictive utility of Insulin-like growth factor-1 receptor (IGF1R), IGF1, IGF2, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and of hemoglobin levels for tumor response to exclusive radiotherapy, in patients with locally advanced Human papillomavirus (HPV) 16-positive cervical cancer. PATIENTS AND METHODS: From 102 patients treated at our institutes, 38 patients with histologically-proven HPV16-positive cervical cancer were included in this prospective case-controlled study. All patients underwent exclusive radiotherapy-only. Complete response was defined as an absence of residual disease at clinical examination and radiological imaging, three months after the completion of treatment. Gene expression levels, assessed before radiotherapy, were compared between responders and non-responders. Controls consisted of normal cervical tissue samples from 30 patients with non-oncological indications. RESULTS: Twenty patients (52.6%) showed a complete response. Gene expressions of IGF1R (34%), IGF2 (24%), and GAPDH (median=3.26 versus 2.12) were increased in cancer patients, in comparison with the control group. Higher levels of expression of GAPDH were observed in patients co-expressing IGF2 and IGF1R, who had a hemoglobin level ≤ 11 g/dl (p=0.05). Clinical characteristics in the responder and in the non-responder groups were similar. In bi-variate and multi-variate analyses, IGF1R expression was the only factor predictive of response to radiotherapy (p=0.018). Accordingly, patients with IGF1R expression had a 28.6-fold greater risk of treatment failure. CONCLUSION: In our study, IGF1R was a strong predictive marker of lack of response to radiotherapy. Larger prospective trials are needed to validate IGF1R as a biomarker of radiation response for patients with HPV16-positive cervical cancer.
