Astrid M Bedoya1, David J Tate2, Armando Baena3, Carlos M Córdoba4, Mauricio Borrero5, René Pareja6, Fredy Rojas6, John R Patterson2, Rolando Herrero7, Arnold H Zea8, Gloria I Sanchez9. 1. Group Infection and Cancer, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia; School of Microbiology, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia. 2. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA70112, USA. 3. Group Infection and Cancer, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia. 4. Group Infection and Cancer, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia; Hospital San Vicente Fundación, Calle 54 No 51D-154, Medellín, Colombia; Department of Gynecology and Obstetrics, School of Medicine, Universidad de Antioquia, UdeA, Calle 70 No 52-52, Medellin, Colombia. 5. Group Infection and Cancer, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia; Department of Gynecology and Obstetrics, School of Medicine, Universidad de Antioquia, UdeA, Calle 70 No 52-52, Medellin, Colombia; Instituto de Cancerología Las Américas, Carrera 70 No 1-35, Torre 5, Medellín, Colombia. 6. Instituto de Cancerología Las Américas, Carrera 70 No 1-35, Torre 5, Medellín, Colombia. 7. Prevention and Intervention Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France. 8. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA70112, USA. Electronic address: azea@lsuhsc.edu. 9. Group Infection and Cancer, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia. Electronic address: sanchezg@medicina.udea.edu.co.
Abstract
INTRODUCTION: Cervical cancer is characterized by an immunosuppressive microenvironment and a Th2-type cytokine profile. Expression of arginase (ASE), the enzyme that converts L-arginine into L-ornithine and urea, is stimulated by Th2-type cytokines. OBJECTIVE: To assess the association of ASE activity and L-Arg metabolism products with cervical cancer. METHODS: Sera of 87 and 41 women with histologically confirmed by colposcopy-directed biopsy SCC and CIN3 respectively and 79 with normal cytology or Low-Grade Squamous Intraepithelial Lesion (LSIL), were evaluated. Cytokines were measured using Milliplex Human cytokine/chemokine kit. Arginase (ASE) activity was determined using an enzymatic assay. Levels of L-arginine, L-ornithine, putrescine and spermine were determined by HPLC. RESULTS: Significantly higher levels of ASE activity were observed in women with CIN3 (age-adjusted OR: 24.3; 95%CI: 3.82-155) and SCC (AOR: 9.8; 95%CI: 2.34-40.8). As expected, possibly due to high levels of ASE activity, higher levels of l-Arg were negatively associated with CIN3 (AOR: 0.03; 95%CI: 0.004-0.19) and SSC (AOR: 0.06; 95%CI: 0.02-0.24). Consistent with the role of ASE in the conversion of L-arginine to L-ornithine and polyamine production therefrom, women with cervical cancer had higher levels of spermine and putrescine. A correlation analysis revealed a significant albeit weak relationship between high levels of IL-10 and high levels of ASE (Pearson r=0.32, p-value=0.003) in women with cervical cancer. CONCLUSION: This study indicates that ASE activity and L-Arg degradation mechanisms of immunosuppression are present in cervical cancer. The results foster research in the design of possible strategies to inhibit ASE activity for therapy of cervical cancer.
INTRODUCTION:Cervical cancer is characterized by an immunosuppressive microenvironment and a Th2-type cytokine profile. Expression of arginase (ASE), the enzyme that converts L-arginine into L-ornithine and urea, is stimulated by Th2-type cytokines. OBJECTIVE: To assess the association of ASE activity and L-Arg metabolism products with cervical cancer. METHODS: Sera of 87 and 41 women with histologically confirmed by colposcopy-directed biopsy SCC and CIN3 respectively and 79 with normal cytology or Low-Grade Squamous Intraepithelial Lesion (LSIL), were evaluated. Cytokines were measured using Milliplex Human cytokine/chemokine kit. Arginase (ASE) activity was determined using an enzymatic assay. Levels of L-arginine, L-ornithine, putrescine and spermine were determined by HPLC. RESULTS: Significantly higher levels of ASE activity were observed in women with CIN3 (age-adjusted OR: 24.3; 95%CI: 3.82-155) and SCC (AOR: 9.8; 95%CI: 2.34-40.8). As expected, possibly due to high levels of ASE activity, higher levels of l-Arg were negatively associated with CIN3 (AOR: 0.03; 95%CI: 0.004-0.19) and SSC (AOR: 0.06; 95%CI: 0.02-0.24). Consistent with the role of ASE in the conversion of L-arginine to L-ornithine and polyamine production therefrom, women with cervical cancer had higher levels of spermine and putrescine. A correlation analysis revealed a significant albeit weak relationship between high levels of IL-10 and high levels of ASE (Pearson r=0.32, p-value=0.003) in women with cervical cancer. CONCLUSION: This study indicates that ASE activity and L-Arg degradation mechanisms of immunosuppression are present in cervical cancer. The results foster research in the design of possible strategies to inhibit ASE activity for therapy of cervical cancer.
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