Tumor Biol. DOI 10.1007/s13277-013-1405-8
RESEARCH ARTICLE
Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer Faruk Tas & Senem Karabulut & Murat Serilmez & Rumeysa Ciftci & Derya Duranyildiz
Received: 12 October 2013 / Accepted: 6 November 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Insulin-like growth factor-1 (IGF-1) and its primary binding protein IGFBP-3 play an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including ovarian cancer. The objective of this study was to determine the clinical significance of the serum levels of IGF1 and IGFBP-3 in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum IGF-1 and IGFBP-3 levels were determined by the solid-phase sandwich ELISA method. Twenty age- and sex-matched healthy controls were included in the analysis. Median age of patients was 56.5 years old (range 22 to 83 years). Majority of the patients had advanced disease (FIGO stage III–IV; 90 %). No significant difference was observed in baseline serum IGF-1 and IGFBP-3 levels between EOC patients and healthy controls (p =0.99 and p =0.80, respectively). The young patients had higher serum IGF-1 and IGFBP-3 concentrations (p =0.04 and p =0.02, respectively). Patients with normal CA-125 levels had higher serum IGFBP-3 concentrations compared with those with higher CA-125 levels (p =0.008). However, no other clinical variables including histology, tumor grade, stage of disease, and response to chemotherapy were found to be correlated with serum IGF assays (p >0.05). A trend to significant relationship was found between the serum levels of IGF-1 and IGFBP-3 (r s =0.212, p =0.07). The patients with elevated serum IGF-1 levels had favorable progression-free and overall survivals than those with lower levels (p =0.04 and p =0.03, respectively). However, serum IGFBP-3 concentrations were found to have no prognostic role for both survivals (p =0.12 and p =0.26, respectively). In conclusion, F. Tas (*) : S. Karabulut : M. Serilmez : R. Ciftci : D. Duranyildiz Institute of Oncology, University of Istanbul, Capa, 34390 Istanbul, Turkey e-mail: [email protected]
elevated serum level of IGF-1 is associated with favorable progression-free and overall survivals in EOC patients. Keywords Serum . IGF-1 . IGFBP-3 . Ovarian cancer . Prognostic factor
Introduction Insulin-like growth factor-1 (IGF-1) is a multifunctional peptide, which plays an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including epithelial ovarian cancer (EOC) [1–10]. In vitro studies show that IGF-1 increases ovarian cell growth and invasive potential, suggesting a role of the IGF-1 pathway in ovarian cancer etiology [1, 2]. Epidemiological data regarding plasma IGF1 levels and EOC risk are conflicting [3]. Two prospective studies observed that plasma IGF-1 levels are associated with an increased risk of EOC among younger women [4, 5], whereas the other study suggested that it may be inversely correlated with EOC risk [6, 7]. These trials report lower IGF1 concentrations in EOC patients compared with healthy women. The insulin-like growth factor binding protein (IGFBP) family of binding proteins consists of six structurally related proteins, and all members are expressed in the normal ovary [10]. Their role is to bind and regulate the effects of the IGFs. IGFBP-3 is the primary binding protein of IGF-1 and regulates the mitogenic and anti-apoptotic actions of IGFs [1–10]. In addition, notably, IGFBP-3 has direct IGF-independent effects on cellular growth and apoptosis. With respect to IGFBPs, prospective studies agree that there are no clear associations of IGFBP-3 with EOC risk [4, 5, 7]. An association between serum levels of this family and the presence of EOC has also been identified [6]. Serum levels of IGFBP-3
Tumor Biol.
are significantly decreased in EOC patients relative to those with benign tumors and healthy controls [6, 11]. Moreover, in EOCs, IGFBP-3 has been associated with disease stage and residual tumor volume when measured by ELISA or by quantitative reverse transcription PCR [12, 13]. The significance of the serological levels of IGF-1 and IGFBP-3 in EOC patients is not known yet. Given the conflicting results from recent epidemiological studies examining the IGF axis and EOC, we conducted this study to test the diagnostic, predictive, and prognostic roles of serum IGF-1 and IGFBP-3 concentrations in EOC patients.
Table 1 Characteristics of the patients and disease
Materials and methods Patients A total of 50 EOC patients with histologically proven diagnosis treated at Istanbul University Institute of Oncology were enrolled into the study. The staging was established in accordance with the International Federation of Gynecologists and Obstetricians (FIGO) classification. Patients with stage III with bulky disease or stage IV disease were initially treated with neoadjuvant chemotherapy and operated afterwards. Patients with operable stage III disease who had undergone primary surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, and pelvic and/or para-aortic lymphadenectomy were treated with adjuvant chemotherapy. All patients received standard paclitaxel–carboplatincontaining chemotherapy regimen. For comparison of serum IGF-1 and IGFBP-3 levels, 20 age- and sex-matched healthy controls were included in the analysis. Informed consent was obtained from all patients, and the study was reviewed and approved by a local ethical committee. Measurement of serum IGF-1 and IGFBP-3 levels Serum samples were obtained on first admission before any adjuvant and metastatic treatment was given and patients were followed up. Blood samples were obtained from EOC patients and healthy controls by venipuncture and clotted at room temperature. The sera were collected following centrifugation and frozen immediately at −20 °C until analysis. Serum IGF-1 (Mediagnost, Germany) and IGFBP-3 (Mediagnost, Germany) levels were determined by the solidphase sandwich ELISA method. The IGF-1 ELISA (Mediagnost, Germany) uses a doubleantibody sandwich enzyme-linked immunosorbent assay to determine the level of human IGF-1 in samples. Serum samples and standards were added to the wells which are precoated with human IGF-1 monoclonal antibody. IGF-1
Variables
Number
No. of patients Age of patients (year)
RESEARCH ARTICLE
Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer Faruk Tas & Senem Karabulut & Murat Serilmez & Rumeysa Ciftci & Derya Duranyildiz
Received: 12 October 2013 / Accepted: 6 November 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Insulin-like growth factor-1 (IGF-1) and its primary binding protein IGFBP-3 play an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including ovarian cancer. The objective of this study was to determine the clinical significance of the serum levels of IGF1 and IGFBP-3 in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum IGF-1 and IGFBP-3 levels were determined by the solid-phase sandwich ELISA method. Twenty age- and sex-matched healthy controls were included in the analysis. Median age of patients was 56.5 years old (range 22 to 83 years). Majority of the patients had advanced disease (FIGO stage III–IV; 90 %). No significant difference was observed in baseline serum IGF-1 and IGFBP-3 levels between EOC patients and healthy controls (p =0.99 and p =0.80, respectively). The young patients had higher serum IGF-1 and IGFBP-3 concentrations (p =0.04 and p =0.02, respectively). Patients with normal CA-125 levels had higher serum IGFBP-3 concentrations compared with those with higher CA-125 levels (p =0.008). However, no other clinical variables including histology, tumor grade, stage of disease, and response to chemotherapy were found to be correlated with serum IGF assays (p >0.05). A trend to significant relationship was found between the serum levels of IGF-1 and IGFBP-3 (r s =0.212, p =0.07). The patients with elevated serum IGF-1 levels had favorable progression-free and overall survivals than those with lower levels (p =0.04 and p =0.03, respectively). However, serum IGFBP-3 concentrations were found to have no prognostic role for both survivals (p =0.12 and p =0.26, respectively). In conclusion, F. Tas (*) : S. Karabulut : M. Serilmez : R. Ciftci : D. Duranyildiz Institute of Oncology, University of Istanbul, Capa, 34390 Istanbul, Turkey e-mail: [email protected]
elevated serum level of IGF-1 is associated with favorable progression-free and overall survivals in EOC patients. Keywords Serum . IGF-1 . IGFBP-3 . Ovarian cancer . Prognostic factor
Introduction Insulin-like growth factor-1 (IGF-1) is a multifunctional peptide, which plays an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including epithelial ovarian cancer (EOC) [1–10]. In vitro studies show that IGF-1 increases ovarian cell growth and invasive potential, suggesting a role of the IGF-1 pathway in ovarian cancer etiology [1, 2]. Epidemiological data regarding plasma IGF1 levels and EOC risk are conflicting [3]. Two prospective studies observed that plasma IGF-1 levels are associated with an increased risk of EOC among younger women [4, 5], whereas the other study suggested that it may be inversely correlated with EOC risk [6, 7]. These trials report lower IGF1 concentrations in EOC patients compared with healthy women. The insulin-like growth factor binding protein (IGFBP) family of binding proteins consists of six structurally related proteins, and all members are expressed in the normal ovary [10]. Their role is to bind and regulate the effects of the IGFs. IGFBP-3 is the primary binding protein of IGF-1 and regulates the mitogenic and anti-apoptotic actions of IGFs [1–10]. In addition, notably, IGFBP-3 has direct IGF-independent effects on cellular growth and apoptosis. With respect to IGFBPs, prospective studies agree that there are no clear associations of IGFBP-3 with EOC risk [4, 5, 7]. An association between serum levels of this family and the presence of EOC has also been identified [6]. Serum levels of IGFBP-3
Tumor Biol.
are significantly decreased in EOC patients relative to those with benign tumors and healthy controls [6, 11]. Moreover, in EOCs, IGFBP-3 has been associated with disease stage and residual tumor volume when measured by ELISA or by quantitative reverse transcription PCR [12, 13]. The significance of the serological levels of IGF-1 and IGFBP-3 in EOC patients is not known yet. Given the conflicting results from recent epidemiological studies examining the IGF axis and EOC, we conducted this study to test the diagnostic, predictive, and prognostic roles of serum IGF-1 and IGFBP-3 concentrations in EOC patients.
Table 1 Characteristics of the patients and disease
Materials and methods Patients A total of 50 EOC patients with histologically proven diagnosis treated at Istanbul University Institute of Oncology were enrolled into the study. The staging was established in accordance with the International Federation of Gynecologists and Obstetricians (FIGO) classification. Patients with stage III with bulky disease or stage IV disease were initially treated with neoadjuvant chemotherapy and operated afterwards. Patients with operable stage III disease who had undergone primary surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, and pelvic and/or para-aortic lymphadenectomy were treated with adjuvant chemotherapy. All patients received standard paclitaxel–carboplatincontaining chemotherapy regimen. For comparison of serum IGF-1 and IGFBP-3 levels, 20 age- and sex-matched healthy controls were included in the analysis. Informed consent was obtained from all patients, and the study was reviewed and approved by a local ethical committee. Measurement of serum IGF-1 and IGFBP-3 levels Serum samples were obtained on first admission before any adjuvant and metastatic treatment was given and patients were followed up. Blood samples were obtained from EOC patients and healthy controls by venipuncture and clotted at room temperature. The sera were collected following centrifugation and frozen immediately at −20 °C until analysis. Serum IGF-1 (Mediagnost, Germany) and IGFBP-3 (Mediagnost, Germany) levels were determined by the solidphase sandwich ELISA method. The IGF-1 ELISA (Mediagnost, Germany) uses a doubleantibody sandwich enzyme-linked immunosorbent assay to determine the level of human IGF-1 in samples. Serum samples and standards were added to the wells which are precoated with human IGF-1 monoclonal antibody. IGF-1
Variables
Number
No. of patients Age of patients (year)
