Insulin-like growth factor-1 and childhood cancer risk
Affiliations: Department of Pediatrics, Faculty of Medicine, Zagazig University, 44111 Zagazig, Egypt, Department of Medical Biochemistry, Zagazig University, Zagazig, Egypt
- Published online on: September 8, 2010 https://doi.org/10.3892/ol.2010.169
- Pages: 1055-1060
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Insulin-like growth factors (IGFs) are polypeptides with a high sequence, similar to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF ‘axis’) consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (IGF-1 and IGF-2), a family of six high-affinity IGF-binding proteins (IGFBP-1 to -6), as well as associated IGFBP-degrading enzymes, referred to collectively as proteases.
It has become increasingly clear that the growth hormone (GH)/IGF-1 axis plays a fundamental and obligatory role in regulating normal somatic growth throughout fetal and childhood development. Over the past two decades considerable evidence has accumulated showing that these growth factors play an important role in maintaining and supporting the progression of neoplastic growth. A number of epidemiological reports showed that it may also be an important determinant of cancer incidence (1).
The risk of cancer is higher among people with elevated concentrations of IGF-1, and is lower among those with high concentrations of IGFBP-3 (the main binding protein). The associations are similar when people whose blood samples were taken shortly before diagnosis are excluded from analyses, suggesting that the observed correlations are not due to the release of the growth factor by preclinical cancers (2).
In adults, numerous studies demonstrated that higher IGF-1 levels are associated with a significantly increased risk of developing a number of the most common types of cancer, such as colon, breast, prostate and possibly lung (3). However, only a few studies have investigated the association between IGF-1 levels and childhood cancer risk. Higher levels of IGF-1 were shown to increase the risk of leukemia in children (4). Additionally, a role has been demonstrated for IGF-1 and other components of the IGF system in the pathogenesis and progression of other childhood malignancies (5).
IGF-1 exerts powerful effects on each of the key stages of cancer development and behavior: cellular proliferation and apoptosis, angiogenesis and metastasis, and more recently, development of resistance to chemotherapeutic agents (6,7).
Given the mounting evidence of the risk of cancer, caution should be exercised in the exogenous use of either IGF-1 or substances that increase its concentration (8).
This study aimed to compare the IGF-1 serum level in children with de novo malignancies to healthy children, and to assess its relationship with cancer type, stage, metastasis and different disease characteristics.
Subjects and methods
This study was conducted in the Pediatric Hematology and Oncology Unit of Zagazig University Hospital and the Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Egypt, during the period from January 2009 to December 2009.
The study included two groups. Group I (patient group) consisted of 50 children with de novo malignancies, whether hematological malignancies or solid tumors. Group II (control group) consisted of 50 age- and gender-matched healthy children as a control group.
Patients were subjected to a routine work-up for their cancers according to our local standards. Estimation of the serum level of IGF-1 in the two groups was carried out using the DRG IGF-1 600 ELISA kit on the Sunrise Remote/Touch ELISA analyzer.
A total of 3 ml of blood was collected by venipuncture and allowed to clot. The serum was then separated by centrifugation at room temperature. Serum samples were frozen at −20°C until the time of assay.
Principle of the test
The DRG IGF-1 600 ELISA kit is a solid phase enzyme-linked immunosorbent assay (ELISA), based on the principle of competitive binding. Patient samples, standards and controls were acidified and neutralized prior to the assay procedure. Microtiter wells were coated with a monoclonal antibody directed towards an antigenic site on the IGF-1 molecule. The pre-treated sample was incubated at room temperature with conjugate (biotinylated IGF-1). The wells were washed and incubated with an enzyme complex (streptavidin-HRP-complex). After addition of the substrate solution, the intensity of the developed color was reverse proportional to the concentration of IGF-1 in the patient sample.
Statement of ethics
The present study was conducted in accordance with the ethical standards of the Helsinki Declaration of 1964, as revised in 2000, and was approved by our local ethics committee. Informed consent was obtained from the study participants or their guardians.
Data were assessed, entered and analyzed using SPSS version 15. Data were expressed as the mean ± standard deviation for quantitative variables, number and percentage for qualitative variables. ANOVA (F test), the Student's t-test, Chi-square test, Kruskall Wallis (K) test and the correlation coefficient (r) were used when appropriate. P<0.05 was considered to indicate a significant difference.
The study was carried out on 100 children: 50 children with de novo malignancies and 50 healthy children of matched age and gender as a control group. The age and gender of the two groups are shown in Table I.
The patient group included 40 children with hematological malignancies and 10 children with solid tumors. Acute leukemia was the most common childhood cancer in our patients accounting for 72.0% of all of the cancer types. Acute lymphoblastic leukemia (ALL) accounted for approximately two thirds of the children with acute leukemia. Lymphoma was the second most common cancer type accounting for 8% of the cancer types. Solid tumors collectively represented 20% of all of the cancers. Neuroblastoma and rhabdomyosarcoma were the most common solid tumors in our patient group. Table II summarizes the different tumor types in our patient group and their relative percentages.
IGF-1 serum levels in the patients and controls
Our results showed that the children with cancer had significantly higher levels of IGF-1 than the healthy controls (mean ± SD was 454.9±85.7 ng/ml for patients and 99.3±44.1 ng/ml for controls (p<0.001) (Fig. 1). Gender and age are significant factors affecting the serum level of IGF-1. Subsequently, we divided our patients into different age and gender groups and found that the cancer patients still had significantly higher serum levels of IGF-1 than the healthy controls of the same age and gender group (Tables III and IV).
Comparison between different age groups of patients and controls with regard to serum levels of IGF-1.
Comparison between different gender groups of patients and controls with regard to serum levels of IGF-1.
IGF-1 serum levels, tumor type, and initial clinical and laboratory data
No statistically significant difference was noted between patients with hematological malignancies and those with solid tumors with regard to the serum levels of IGF-1 (P=0.52) (Fig. 2). Additionally, no relationship was found between IGF-1 levels and any of the initial clinical and laboratory data including the overall risk of the patients.
No statistically significant difference was found between patients with hematological malignancies and those with solid tumors with regard to serum levels of IGF-1.
IGF-1 serum levels and different ALL immunophenotypes
Although T-ALL patients had higher serum levels of IGF-1 than those with other immunophenotypes, the difference was not statistically significant (P=0.61).
IGF-1 serum levels and different French-American-British (FAB) subtypes in ALL and acute myeloid leukemia (AML)
No significant relationship was noted between the serum levels of IGF-1 and FAB subtypes in the patients with acute leukemia (P=0.18 and 0.45, respectively).
IGF-1 serum levels and metastasis in solid tumors
Although patients with metastatic solid tumors had higher serum levels of IGF-1 as compared to those without metastasis, the difference was not statistically significant (P=0.6) (Fig. 3).
Although the patients with metastatic solid tumors had higher serum levels of IGF-1 than those without metastasis, the difference was not statistically significant.
IGF-1 serum levels and different stages of solid tumors
No significant relationship was found between the serum levels of IGF-1 and different stages of solid tumors (P=0.23).
Since its identification, there have been unresolved concerns about the potential cancer-enhancing properties of IGF-1. Circumstantial evidence in support stems from various sources: in vitro studies, animal studies, epidemiological observations within the general population and patients with growth hormone (GH) excess and deficiency, as well as from the therapeutic manipulation of GH and IGF-1 actions (9).
Considerable epidemiological data have suggested a possible link between circulating GH and/or IGF-1 levels and the development of a variety of different cancer types. Numerous studies suggested that subjects with serum IGF-1 levels that are in the higher percentiles of the normal range have a significantly increased risk of developing a number of the most common types of cancer, such as colon, breast, prostate and possibly lung (3). However, only a few studies have investigated the correlation between IGF-1 levels and childhood cancer risk.
Our results showed that children with cancer had significantly higher levels of IGF-1 than healthy controls. Based on the fact that serum levels of IGF-1 are affected by age and gender, this relationship was examined in different age and gender groups. We found that cancer patients showed significantly higher serum levels of IGF-1 than healthy controls of the same age and gender group.
The relationship between higher levels of IGF-1 and cancer can be explained by the fact that IGF-1 is a potent proliferative agent affecting almost every cell type and also a powerful antiapoptotic agent affecting apoptotic responses to a variety of agents of numerous cell types. These two effects result in a state of hyperproliferation. Such an imbalance between cell proliferation and death would favor, even slightly, the survival of stem cells that had undergone early genetic ‘hits’. Thus, the pool of damaged cells available for second and subsequent hits are likely to increase (10).
Whether IGF-1 is a causal factor or simply a surrogate measure of the malignant process remains unknown. A study by Ma et al (2) showed an association between colorectal cancer risk in men and elevated plasma levels of IGF-1 by using plasma samples drawn over a long period of time prior to the clinical appearance of the tumors. Thus, the possibility that plasma levels were affected by the disease process was minimized, thereby confirming the causal relationship between IGF-1 and cancer.
Numerous studies have investigated the role of IGF-1 in hematological malignancies and solid tumors (5). However, no study thus far has compared the levels of IGF-1 in the two tumor types.
In our study, no differences were noted between hematological malignancies and solid tumors and between ALL and AML patients with regard to the serum level of IGF-1, confirming that IGF-1 levels are higher in cancer patients regardless of their cancer type. Additionally, no association was found between IGF-1 levels and different FAB subtypes in ALL and AML patients. In ALL patients, no relationship was found between IGF-1 levels and different immunophenotypic subtypes.
High levels of IGF-1 have been shown to increase proliferative stress on progenitor cells in bone marrow (4,11), increasing the number of cell divisions and, in turn, the risk of leukemia. Further evidence supports a role for IGF-1 in the pathogenesis of leukemia: IGF-1 receptors were found to be expressed on leukemic lymphoblasts; IGF-1 stimulated the growth of leukemic cells in vitro (12); IGF-1 has been shown to protect hematopoietic cells from apoptosis (13); and the administration of GH, the effect of which is mediated through the IGF-1 system (14), has been reported to increase the risk of childhood acute leukemia (15).
Accelerated fetal growth may be a risk factor for childhood ALL, a tenet supported by evidence that is related to increased levels of IGF-1. In a recent study, McLaughlin et al (16) reported an increased risk of ALL among children with birth weights greater than 3,500 g.
Rangel et al (17) also showed that the estimated risk for certain types of cancer has been found to be statistically and significantly higher with a birth weight of more than 4,000 g (The estimated risk was 1.86 for leukemia, 1.99 for non-Hodgkin's lymphoma and 4.76 for Wilms' tumor).
Contrary to our results, Petridou et al (14) reported that there was no significant association between IGF-1 and the likelihood of childhood leukemia. However, these authors found that an increment of 1 μg/ml of IGFBP-3 was associated with a substantial and statistically significant reduction in childhood leukemia by 28%. Since IGFBP-3 is essentially a binding protein, these findings suggest that bioavailable IGF-1 plays an important role in the etiology of childhood leukemia.
The role of IGF-1 and other components of the IGF system in the pathogenesis and progression of other childhood malignancies have been investigated (5). In lymphoma, IGF-1 has been shown to stimulate the proliferation of T-cell lymphoma lines that have phenotypic characteristics of thymic pre-T cells and to inhibit cell differentiation, which may crucial in early lymphoma tumorigenesis (18). Moreover, IGF-1 causes a significant increase in the proliferation of Burkitt's lymphoma cells, which may be blocked by antiserum against IGF-1 (19).
IGF-2 plays a role as both an autocrine and a paracrine growth factor in neuroblastoma (20,21). High levels of IGF-1 have been shown to play an important role in the pathogenesis of osteosarcoma (22). Northern blot analysis of tumor biopsy specimens from patients with alveolar and embryonal rhabdomyosarcoma showed high levels of IGF-2 mRNA expression, suggesting the possibility that the upregulation of IGF-2 plays a role in the unregulated growth of these tumors (23). The role of IGF-1R signaling in Ewing's sarcoma family of tumors (ESFT), including primitive neuroectodermal tumors, has been evaluated extensively. EFST cell lines were shown to express IGF-1R and secrete IGF-1. IGF-1R-blocking antibodies were shown to be successful in the interruption of this autocrine loop (24,25). Inactivation of WT1, a tumor-suppressor gene, has been shown to up-regulate a number of components of the IGF system that contribute to inappropriate proliferation and development of Wilms' tumor (26–28).
A role for the IGF system in cancer metastasis has recently been documented in various types of human cancer. Barozzi et al (29) found that the overexpression of IGF-2 was predictive of liver metastasis in patients with colorectal cancer. Hakam et al (30) showed a stepwise increase in the expression of IGF-1R during the progression from colonic adenomas towards primary colorectal adenocarcinomas and metastases. In our study, although the serum levels of IGF-1 were higher in metastatic solid tumors than non-metastatic ones, the difference was statistically non-significant.
In conclusion, the IGF-1 serum level is an important indicator of risk for the most prevalent forms of childhood cancer and may be used to both identify children at the highest risk for these cancers and, aid in determining who may benefit most from preventive strategies. Given the small number of children in our study, studies with larger populations are required to confirm these results.
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