Reactivation of the insulin-like growth factor-Ⅱ signaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor （IGF）-signaling axis is frequently observed in human hepatocellular carcinoma （HCC）. Especially the overexpression of the fetal growth factor IGF-Ⅱ, IGF-Ⅰ receptor （IGF-IR）, and cytoplasmic downstream effectors such as insulin-receptor substrates （IRS） contribute to proliferation, anti-apoptosis, and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱ signaling during HCC development and progression. Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies, various experimental strategies have been developed, including neutralizing antibodies and selective receptor kinase inhibitors, with respect to the specific and efficient reduction of oncogenic IGF- Ⅱ/IGF-IR-signaling.     

Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.     

类胰岛素生长因子与肝癌

肝癌是常见的恶性肿瘤之一,其病程快且预后很差.其发生是一个多因素多步骤协同的复杂过程.近来的研究报道,肝癌发生分子机制与类胰岛素生长因子体系信号通路异常相关,类胰岛素生长因子是一种多功能细胞增殖调控因子,他在胚胎发育、中枢神经系统发育及肿瘤细胞增殖等方面具有重要的生物学功能.类胰岛素生长因子的生物学活性受到包括类胰岛素...     

Reactivation of the insulin-like growth factor-Ⅱ signaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma (HCC). Especially the over-expression of the fetal growth factor IGF-Ⅱ, IGF-Ⅰ receptor (IGF-IR), and cytoplasmic downstream effectors such as insulin-receptor substrates (IRS) contribute to proliferation, anti-apoptosis, and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱ signaling during HCC development and progression. Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies, various experimental strategies have been developed, including neutralizing antibodies and selective receptor ki-nase inhibitors, with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.     

Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.     

Specific metabolic biomarkers as risk and prognostic factors in colorectal cancer

Advances in genomics,molecular pathology and metabolism have generated many candidate biomarkers of colorectal cancer with potential clinical value.Epidemiological and biological studies suggest a role for adiposity,dyslipidaemia,hyperinsulinemia,altered glucose homeostasis,and elevated expression of insulin-like growth factor(IGF)axis members in the risk and prognosis of cancer.This review discusses some recent past and current approaches being taken by researches in obesity and metabolic disorders.The authors describe three main systems as the most studied metabolic candidates of carcinogenesis:dyslipidemias,adipokines and insulin/IGF axis.However,each of these components is unsuccessful in defining the diseases risk and progression,while their co-occurrence increases cancer incidence and mortality in both men and women.     

人肝癌胰岛素样生长因子2基因的表达和印迹状态的改变

目的 研究人肝细胞性肝癌(HCC)的发生与胰岛素样生长因子2(IGF2)的表达及其印迹变化之间的关系。方法 采用RT-PCR半定量法和限制性酶切片断长度多态性分析法(RFLP),对40例HCC组织标本(其中33例有癌旁组织),检测IGF2的相对表达量,观察肝癌组织中IGF2基因印迹状态的改变。结果 HCC中IGF2的相对表达量,在各病例间的变化较大;癌组织中的表达(1.5431±1.4316)明显高于癌旁肝组织(0.6517±0.6666),t=3.695,P<0.001;癌组织和癌旁组织均有病例发生基因印迹丢失(LOI)。结论 HCC的发生与IGF2的异常表达增高有关;IGF2的LOI可能是HCC的癌前表现之一。     

Role of the IGF/insulin system in longevity

Human life expectancy is influenced by multiple determinants, including various environmental and genetic factors. Though the non-genetic factors are important, it is estimated that approximately 25-32% of the overall difference in human lifespan for survival after the age of 60 years depends on for by genetic polymorphisms among individuals. In addition, there are human homologues to many genes that affect lifespan in model organisms. In people, longevity genes might slow the rate of age-related changes in cells, increase resistance to environmental stresses like infection and injury, and reduce the risk of many age-related conditions. The best studied longevity pathway is probably the one involving insulin/IGF-1 signaling. The important role of IGF and insulin-related signaling pathways in the control of longevity of worms and insects is very well documented. In the mouse, several spontaneous or experimentally induced mutations that interfere with GH/IGF axis modulation lead to extended longevity. Increases in the average life span in these mutants range from approximately 20-70% depending on the nature of the endocrine defect, gender, diet, and/or genetic background. All the data in animals models and in the population studies support the evidence that this pathway drives an evolutionarily conserved network that regulates lifespan and affects longevity across species. Results obtained in humans are still controversial and further extensive studies are required to firmly establish a role of the IGF1 axis in modulation of human longevity. A better knowledge of the role of this pathway in humans may assist in the design of improved treatment methods for age-related diseases, delay the aging process and prolong the human lifespan.     

The insulin-like growth factor system and the fetal brain: Effects of poor maternal nutrition

The insulin-like growth factor (IGF) signaling system plays indispensable roles in pre- and post-natal brain growth and development. A large body of studies using both in vivo null mutant and transgenic mice and in vitro neuronal culture techniques indicate that IGF-I acts directly on the brain while IGF-II effects are mediated to a large extent by IGF-II control of placental growth. It appears that all of the mechanisms, except migration, that are involved in normal brain development, e.g., proliferation, apoptosis, maturation and differentiation, are influenced by IGF-I. While IGF system members are produced in the brain, recent reports in post-natal animals indicate that normal brain health and function are dependent upon transfer of circulating IGF-I from the liver and its transfer across the blood brain barrier. Data showing that this phenomenon applies to pre-natal brain growth and development would make an important contribution to fetal physiology. A number of kinase pathways are able to participate in IGF signaling in brain with respect to nutrient restriction; among the most important are the PI3K/AKT, Ras–Raf–MEK–ERK and mTOR-nutrient sensing pathways. Both maternal and fetal IGF-I peripheral plasma concentrations are greatly reduced in nutrient restriction while IGF-II does not appear to be affected. Nutrient restriction also affects IGF binding protein concentrations while effects on the IGF-I receptor appear to vary with the paradigm. Studies on the effects of nutrient restriction on the fetal primate brain in relation to activity of the IGF system are needed to determine the applicability of rodent studies to humans.     

Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis

The protumorigenic insulin-like growth factor (IGF)-II is highly expressed in a significant fraction of human hepatocellular carcinomas (HCC). However, a functional dissection that clarifies the contribution of IGF-II-binding receptors in tumor progression and a respective molecular characterization of IGF-II signaling has not been performed. Therefore, expression of IGF-II and its receptors IGF-receptor type I (IGF-IR) and insulin receptor (IR) was efficiently blocked using small interfering RNA (siRNA) in HCC cells. Despite functional IR-signaling, oncogenic IGF-II effects such as tumor cell viability, proliferation, and anti-apoptosis were solely transmitted by IGF-IR. Although IGF-II signaling was previously not described in the context of HCC cell migration, the IGF-II-dependent expression profile displayed a high percentage of genes involved in cell motility and adhesion. Indeed, IGF-II overexpression promoted HCC cell migration, especially in synergy with hepatocyte growth factor (HGF). The therapeutic relevance of IGF-II/IGF-IR signaling was tested in vitro and in a murine xenograft transplantation model using the IGF-IR inhibitor picropodophyllin (PPP). IGF-IR inhibition by small molecule treatment efficiently reduced IGF-II-dependent signaling and all protumorigenic properties of the IGF-II/IGF-IR pathway. CONCLUSION: In human HCC cells, IGF-IR but not IR is involved in oncogenic IGF-II signaling. Autocrine stimulation of IGF-II induces HCC motility by integration of paracrine signals for full malignant competence. Thus, activation of IGF-II/IGF-IR signaling is likely a progression switch selected by function that promotes tumor cell dissemination and aggressive tumor behavior.     

Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G(1) cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the kidney were histologically accurate and exhibited significantly elevated insulin-like growth factor-mediated signaling, and growth was significantly reduced on treatment with NVP-AEW541 in parallel with signaling pathway ablation. As a result of the paracrine effects of enhanced IGF2 expression in Wilms tumor, this disease may be acutely dependent on signaling through the IGF1 receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such efficacy may be missed if only standard ectopic models are considered as a result of an imperfect recapitulation of the specific tumor microenvironment.     

The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge

Background The insulin-like growth factor system, which includes insulin-like growth factors (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR) and IGF binding proteins (IGFBPs), plays an important role in epithelial growth, anti-apoptosis and mitogenesis. There is a growing body of evidence showing that IGFs control growth and proliferation of several types of cancer. This review introduces the latest information on the biology of the IGF system and its pathophysiological role in the development of colorectal cancer.Discussion The growth promoting effects of IGF-I and IGF-II on cancer cells are mediated through the IGF-IR, which is a tyrosine kinase and cancer cells with a strong tendency to metastasise have a higher expression of the IGF-IR. Most of the IGFs in circulation are bound to the IGFBPs, which regulate the bioavailability of the IGFs. All IGFBPs inhibit IGF action by high affinity binding, while some of them also potentiate the effects of IGFs. Colon cancer cells produce specific proteases that degrade the IGFBP so that the IGF will be free to act on the cancer cell in an autocrine manner. Therefore, the IGFBPs play a crucial role in the development of the cancer.Conclusion The current knowledge about the link between IGFs and colon cancer is mainly based on in vitro investigations. Further in vivo study is needed to understand the exact role of the IGF system, especially its binding proteins, so that they can be manipulated for the prevention and treatment of colorectal cancer.     

Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line

In diabetic nephropathy, glomerular mesangial cells exhibit aberrant anabolic activity that includes excessive production of extracellular matrix (ECM) proteins, leading to crowding of filtration surface areas and possible renal failure. In the present study, a murine mesangial cell line (MES-13 cells) was studied to determine the roles of the renin-angiotensin system (RAS) and the insulin-like growth factor (IGF) axis in the anabolic response to elevated glucose levels. Culture of MES-13 cells in medium containing supra-physiological glucose concentrations (>5.5 mmol/l) resulted in increased production of ECM proteins including laminin, fibronectin, and heparan sulfate proteoglycan with concurrent increases in IGF-binding protein (IGFBP)-2 production. These responses were blocked by the angiotensin receptor antagonists saralasin and losartan, while exogenous angiotensin II (Ang II) treatment directly stimulated increases in ECM and IGFBP-2. In all experiments, IGFBP-2 levels were correlated with anabolic activity implicating IGFBP-2 as a possible mediator in cellular responses to high glucose and Ang II. Such mediation appears to involve IGFBP-2 modulation of IGF-I signaling, since all responses to high glucose or Ang II were blocked by immuno-neutralization of IGF-I. These data suggest alterations in the IGF axis as key mechanisms underlying nephropathic responses of mesangial cells to Ang II and high glucose.     

A candidate targeting molecule of insulin-like growth factor-I receptor for gastrointestinal cancers

Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage.One new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) carcinomas.The concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new drugs.Type I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human malignancies.In this review,we focus on this promising therapeutic target,IGF-IR.The IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI cancers.Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments.These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and pancreas.We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences.Several mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single agents.We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug combinations.Thus,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas.     

Role of insulin／insulin-like growth factor I signaling pathway in longevity

The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse species including C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegans to humans. The role of insulin/IGF-1 in longevity is probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.     

Time course of the GH/IGF axis response to fasting and increased ration in chinook salmon (Oncorhynchus tshawytscha)

Body growth in vertebrates is chiefly regulated by the GH/IGF axis. Pituitary growth hormone (GH) stimulates liver insulin-like growth factor-I (IGF-I) production. During fasting, plasma IGF-I levels decline due to the development of liver GH resistance, while GH levels generally increase. In mammals, decreased insulin during fasting is thought to cause liver GH resistance. However, the sequence of events in the GH/IGF axis response to fasting is not well characterized, especially in non-mammalian vertebrates. We assessed the time course of the GH/IGF axis response to fasting and increased ration in chinook salmon. Fish were placed on Fasting, Increased, or Control rations, and sampled daily for 4 days and at more widely spaced intervals through 29 days. Plasma IGF-I, GH, insulin, and 41 kDa IGF binding protein (putative salmon IGFBP-3), and liver IGF-I gene expression were measured. Control and Increased ration fish did not differ strongly. Plasma IGF-I and 41 kDa IGFBP were significantly lower in Fasted versus Control fish from day 4 onward, and liver IGF-I gene expression was significantly lower from day 6 onward. Liver IGF-I gene expression and plasma IGF-I levels were correlated. Plasma insulin was lower in Fasted fish from day 6 onward. There was a trend toward increased GH in Fasted fish on days 1-2, and GH was significantly increased Fasted fish from day 3 onward. Fasted GH first increased (days 1-3) to a plateau of 10-20 ng/ml (days 4-12) and then increased dramatically (days 15-29), suggesting that the GH response to fasting had three phases. The early increase in GH, followed by the decrease in plasma IGF-I after 4 days, suggests that GH resistance developed within 4 days.