胰岛素样生长因子家族在肿瘤中的作用研究进展

胰岛素样生长因子（insulin-like growth factors,IGFs）家族的研究是当今细胞生物领域的热点,日益受到重视。IGFs家族由IGF及其受体和胰岛素样生长因子结合蛋白（insulin-like growth factor binding protein,IGFBP）组成。IGFs家族是一类多功能细胞增殖调控因子,它们调控细胞的生长和增殖。IGFs在结构上与胰岛素稍微不同,它包含一个额外的结构域,这可能是它与胰岛素在肿瘤中起到的作用也不相同的原因[1]。在细胞水平,IGFBP被证明调节细胞分化、生长和凋亡[2]。IGFBP通过与IGFs相结合来调节其生物活性,并以结合物的形式释放在人体器官[3],也可以通过非依赖性机制抑制或促进IGF的作用。最近,IGFs家族显示出它在中发展进程中起到重要的作用,同时也是一个潜在的治疗靶向[1]。     

胰岛素样生长因子Ⅰ（IGF-Ⅰ）与各疾病的相关性研究进展

胰岛素样生长因子（IGFs）作为一类多功能细胞增殖调控因子,是一种在分子结构上与胰岛素类似的多肽蛋白物质,又称类胰岛素生长因子。其由两类物质组成,即 IGF-Ⅰ和 IGF-Ⅱ。     

血清胰岛素样生长因子1及结合蛋白3在食管癌患者中的表达及意义

胰岛素样生长因子系统（IGFs）及其结合蛋白与肿瘤的关系是近年研究的热点，动物及细胞实验也证明IGFs是促肿瘤生长因子，而胰岛素样生长因子结合蛋白3（IGFBP-3）则表现出对肿瘤的抑制作用。越来越多的研究表明胰岛素样生长因子1（1GF-1）和IGFBP-3在多种肿瘤中发挥着重要的作用。本研究通过对比22例食管癌患者和15例健康人以及14例化疗有效患者血清中IGF-1和IGFBP-3的含量，研究其与食管癌发生发展及化疗疗效的关系。     

IGFBPs家族基因遗传变异与乳腺癌关系的研究进展

胰岛素样生长因子(insulin-like growth factors,IGFs)是一类与胰岛素呈高度同源的细胞增殖调控因子,是一种可促进细胞增殖和分化的多肽。IGFs系统是一个由一系列相关分子构成的复杂网络,其中包括了配体(IGF-1和IGF-2)、细胞表面受体(IGF-1R、IGF-2R及IR)、IGFs结合蛋白(IGF-binding proteins,IGFBPs)和一组IGFBPs蛋白酶。     

胰岛素样生长因子系统与运动系统的关系研究进展

胰岛素样生长因子系统（insulin-like growth factor.IGFs）是一个复杂的体系，其构成主要包括：IGF-Ⅰ、IGF-Ⅱ、IGFBPI-6（骨骼组织主要为IGFBP3-5）、IGF-IR，酸不稳定亚单位等成分。许多组织、细胞在不同的发育阶段都有IGF-Ⅰ和IGF-Ⅱ的表达，而骨骼是除了肝脏之外血IGFs的第二大来源。IGFs生物学作用广泛，不仅能模拟生长素的一些生物学效应，同时也具有类似胰岛素的代谢活性，对多个器官组织有生物学功能。     

胰岛素样生长因子-Ⅰ对血管平滑肌细胞的作用机制

高血压、动脉粥样硬化、血管再通术后的狭窄等一系列血管增生性疾病威胁着人类健康,并有上升趋势。血管平滑肌细胞（VSMC）的异常增殖和从血管中膜向血管内膜定向迁移,在这些血管增生性疾病中起决定性作用。在众多影响VSMC增殖导致血管内膜增生的因子中最重要的因素之一是胰岛素样生长因子（IGFs）。而IGFs中胰岛素样生长因子Ⅰ（IGF-Ⅰ）在调节VSMC增殖、定向迁移、分化和凋亡起着尤为重要的作用。笔者就IGF-Ⅰ对血管平滑肌细胞的作用机制作一综述。     

IGF-1及其在糖尿病中的应用

胰岛素样生长因子(Insulin like growth factors,IGFs)由Salmon和Daughaday于1957年首先发现,在生长激素(GH)作用过程中起介导作用,故被称为生长介素(somatomedin)。1978年被正式命名为IGFs,并划分为IGF-1和IGF-2二类。它们几乎存在于哺乳动物的所有组织中,与胰岛素有相似的结构,是一类具有细胞分化和增殖功能,并具有胰岛素样作用的多肽。以下简要综述近年来IGF-1及其在糖尿病中应用的新进展。 1 IGF-1结构、受体及其结合蛋白     

胰岛素样生长因子与慢性肾功能衰竭患者营养不良的关系

营养不良导致了慢性。肾功能衰竭(CRF)患者的并发症高发生率和高死亡率。而研究表明，胰岛素样生长因子(insulin-like growth factor，IGFs)参与了机体的多种物质代谢，与CRF并发营养不良有关。现将这方面的进展综述如下。     

胰岛素样生长因子与慢性肾功能衰竭患者营养不良的关系

营养不良导致了慢性肾功能衰竭(Chronic renal failure．CRF)患者的并发症高发生率和高死亡率，而研究表明，胰岛素样生长因子(insulin-like growth factor，IGFs)，参与机体的多种物质代谢，与CRF并发营养不良有关。现将这方面的进展综述如下。     

胰岛素样生长因子对骨的作用及运动对其的影响

对胰岛素样生长因子（IGFs)与骨形成，骨重建的关系以及运动对其的影响进行了分析了综述和分析表明，IGF－1，不仅可以促进成骨细胞的骨形成作用，还可以促进破骨细胞的骨吸收作用，从而在骨的重建起着重要的作用；对于运动能否导致血清IGFs浓度升高，众多研究结果出现了分支，这种是由于研究方法，训练方式及运动强度不同所致，因此，还需要对此进行更多更规范的研究以得出一个肯定的结果。     

IGFs and IGF-binding proteins as diagnostic markers and biological modulators in brain tumors

The insulin-like growth factors (IGFs) play a pivotal role in brain tumor growth and inhibition of apoptosis. Specific IGF binding proteins (IGFBPs) may enhance or inhibit tumor growth. Moreover, IGFBPs represent tumor markers and their expression correlates with tumor grading and patient survival. Understanding the role IGFs play for the proliferation of brain tumors is a prerequisite for modulating the biology of tumorigenesis. Novel antisense strategies targeting IGF-I or the Type I IGF receptor may offer additional options to patients suffering from malignant gliomas and other CNS malignancies. Clinical trials are currently underway that should demonstrate whether a beneficial effect is achievable in these patients.     

Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation.

Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an important role in cell growth and differentiation. Clinical and epidemiological studies have indicated that measuring IGFs and IGFBPs in blood has potential implications in assessing growth-related abnormalities and risks of certain types of cancer. To facilitate the application, we reported a large collection of reference ranges of IGFs and IGFBPs in normal population and evaluations of these molecules in serum and plasma as well as the impact of freeze-thaw cycles on the measurement. IGF-I, IGFBP-3 andALS showed a similar pattern of change associated with age. Levels of these molecules were low at birth and increased with age through puberty. After puberty the levels declined slowly with age. Overall, IGF-I, IGFBP-3 and ALS were slightly higher in females than in males. Free IGF-I accounted for about 1% of the total IGF-I and its variation with age was similar to total IGF-I. IGF-II levels were also increased with age from birth to puberty, but became stable after puberty. There was little difference in IGF-II levels between genders. IGFBP-2 levels declined with age from birth to puberty. Levels of IGFBP-6 in contrast were increased with age. These IGF binding proteins were higher in males than in females. IGFs, IGFBP-3 and ALS were 5-10% higher in serum than in plasma. IGFBP-2 and IGFBP-6 differed substantially between serum and plasma. Freeze-thaw treatment up to five cycles had little impact on plasma levels of IGFs and IGFBP-3. Our observations suggest that levels of IGFs and their binding proteins are varied with age, gender, and types of specimen and that these variations need to be taken into consideration when IGFs and their binding proteins are utilized in clinic and research.     

Associations of blood levels of insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-3 in schizophrenic Arab subjects.

BACKGROUND: Insulin-like growth factors (IGFs) are believed to be important in brain development and repair following neuronal damage. It is also speculated that IGFs are involved in the association of foetal and pre-adult growth with schizophrenia (SZ). METHODS: The aim of this study was to assess levels of IGF-I, IGF-II and IGF binding protein (IGFBP)-3 and their associations in male Arab patients with SZ (n=53) and healthy control subjects (HC; n=52). Anthropometric and demographic data were collected for each subject for whom blood specimens were analysed for serum lipoproteins, apolipoprotein B (apoB), IGF-I, IGF-II and IGFBP-3. RESULTS: The SZ group had lower serum total cholesterol, apoB and uric acid levels than the HC group (p<0.05). IGF-II levels were significantly higher in the SZ group (p=0.02) and correlated positively with levels of atherogenic lipoproteins--total cholesterol, low-density lipoprotein, apoB--and IGFBP-3. The pattern of correlations between the IGFs and the various parameters differed somewhat between the HC and SZ groups. CONCLUSIONS: These results demonstrate that IGF-II levels are increased in patients with SZ and show significant associations with atherogenic lipoproteins. We suggest a possible link between IGF-II metabolism and atherogenesis in SZ.     

Demonstration of the production and physiological role of insulin-like growth factor II in rat thyroid follicular cells in culture.

Insulin-like growth factors (IGFs) are potent mitogens for FRTL5 rat thyroid follicular cells. IGFs also synergize the independent mitogenic effects of thyrotropin-stimulating hormone (TSH) and other agents that increase intracellular AMP concentration. We examined whether FRTL5 cells and M12 cells, a TSH-independent mutant cell line derived therefrom, secrete IGF that regulates the growth of rat thyroid follicular cells. Immunoreactive IGF-II, but not IGF-I, was found in media conditioned by FRTL5 cells; media from M12 cells contained four- to fivefold higher concentrations. Medium conditioned by FRTL5 and M12 both stimulated [3H]thymidine incorporation in FRTL5 and amplified the mitogenic effects of TSH. M12-conditioned medium was more potent than FRTL5-conditioned medium. Sm-1.2, a monoclonal antibody that recognizes IGF-I and IGF-II but not insulin, inhibited basal DNA synthesis in FRTL5 and M12 cells and the mitogenic effects in FRTL5 of agents that are synergized by IGF, such as TSH, forskolin, Bt2cAMP, and Graves'-IgG. Sm-1.2 did not inhibit the mitogenic response to insulin. Thus, rat insulin-like growth factor II (rIGF-II) is an autocrine growth factor that regulates FRTL5 growth, in part by amplifying the mitogenic response to TSH. Results with M12 cells raise the possibility that endogenous rIGF-II may partially mediate the TSH-independent growth of these cells.     

Insulin-like growth factors and pancreas beta cells

Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signalling pathways for pancreas beta-cell development, and for type 2 diabetes. Insulin-like growth factor-I signalling has a lot in common with insulin signalling, and is involved in diverse cellular effects such as antiapoptosis, protein synthesis, cell growth and mitogenesis. Insulin-like growth factor-II can be bound by the insulin receptor A subtype and the IGF-1 receptor, which may explain its antiapoptotic effect. Various knock-out model studies indicate that absence of IGF-I or the IGF-1 receptor is critical for foetal and postnatal growth. Similarly, knock-out models of post-receptor molecules (such as IRS-2) point to the physiological role of IGFs for pancreas beta-cell development. A beta-cell-specific IGF-1 receptor knock out model indicates the importance of IGF-I for beta-cell function. The Goto-Kakizaki (GK) rat, a model for diabetes, has insufficient beta-cell development, which may be related to its defective IGF-II synthesis. As normal pancreas beta cells adapt to the prevailing insulin resistance with increasing beta-cell function, it is possible that insulin resistance interacts with IGF signalling in pancreas beta cells.     

Regulation of binding proteins for insulin-like growth factors (IGF) in humans. Increased expression of IGF binding protein 2 during IGF I treatment of healthy adults and in patients with extrapancreatic tumor hypoglycemia.

Insulin-like growth factors (IGFs) in blood form two complexes with specific binding proteins (BPs): a large, growth hormone (GH)-dependent complex with restricted capillary permeability, and a smaller complex, inversely related to GH, with high turnover of its IGF pool and free capillary permeability. The distribution of BPs and of IGFs I and II between these complexes was studied in sera from healthy adults treated with IGF I or/and GH and from patients with extrapancreatic tumor hypoglycemia. Like GH, IGF I administration raises IGF I and two glycosylation variants of IGFBP-3 in the large complex, but unlike GH drastically reduces IGF II. During IGF I infusion, IGFBP-3 appears in the small complex whose IGFBP-2 and IGF I increase three- to fivefold and fivefold, respectively. GH treatment, associated with elevated insulin levels, suppresses IGFBP-2 and inhibits its increase owing to infused IGF I. The small complex of tumor sera contains increased amounts of IGFBP-2 and -3, and two- to threefold elevated IGF II. Conclusions: low GH and/or insulin during IGF I infusion and in extrapancreatic tumor hypoglycemia enhance expression of IGFBP-2 and favor partition of IGFBP-3 into the small complex. Free capillary passage and high turnover of its increased IGF I or II pools may contribute to compensate for suppressed insulin secretion during IGF I infusion or to development of tumor hypoglycemia.     

Insulin-like growth factors in patients with liver cysts

Insulin-like growth factors (IGFs) play an important role in cell growth and differentiation, and the liver is the main source of IGFs and IGF-binding proteins (IGFBPs) that appear in the circulation. The effect of liver cysts on the circulating IGF system was studied in this work. Serum concentrations of IGF-I and -II were measured by radioimmunoassay, IGFBP patterns were characterised by ligand-affinity and immunoblotting, and a lectin-binding assay was used to investigate the glyco component of IGFBP-3 complexes. IGF-I and -II concentrations in patients with cysts were significantly lower compared to those in healthy individuals (P<0.0001 and P<0.01, respectively), and the decrease was related to age but not sex. The overall mean concentrations of IGF-I and -II were not significantly different whether the cysts were caused by Echinococcus granulosus, cross-reactive pathologies, or some other factor. IGFBP profiles correlated with the amount of IGF present: patients with lower IGF-I concentrations expressed decreased IGFBP-3 and elevated IGFBP-2 levels. Increased IGFBP-3 proteolytic activity in the patients' blood was not detected by immunoblotting. In the lectin-binding assay, IGFBP-3 complexes in the circulation of patients demonstrated reactivity similar to that in healthy persons, suggesting that the overall structure of the saccharide moieties of the IGFBP-3 complexes was not significantly altered due to liver cyst formation.     

Circulating levels of IGF-1 directly regulate bone growth and density

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.     

Decreased trabecular bone biomechanical competence, apparent density, IGF-II and IGFBP-5 content in acromegaly

BACKGROUND: Earlier studies on the effect of excess growth hormone (GH) on trabecular bone have been conflicting. Since insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in part mediate the effects of GH, the present study aimed to investigate trabecular bone composition of these growth factors in relation to biomechanical properties in acromegaly. MATERIALS AND METHODS: Trabecular bone biomechanical competence (compression test), apparent density (peripheral quantitative computed tomography, pQCT), and bone matrix contents of calcium (HCl hydrolysis) and IGFs (guanidinium-HCl extraction) were measured in iliac crest biopsies from 13 patients with active acromegaly (two women and 11 men, aged 21-61 years) and 21 age- and sex-matched controls (four women and 17 men, aged 23-64 years). RESULTS: Trabecular bone pQCT was reduced in acromegalic patients compared with controls (P = 0.005), as was biomechanical competence (P < 0.05 for all measures). These parameters were significantly positively correlated in both acromegalic patients and controls. The calcium content of trabecular bone was significantly increased in patients compared with controls. No significant differences were found in trabecular bone content of IGF-I, IGFBP-3, or osteocalcin. However, IGF-II and IGFBP-5 content was decreased (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: The present study demonstrates reduced trabecular biomechanical competence and apparent density in acromegaly, supporting previous observations of an unfavourable effect of chronic excess GH on the axial skeleton. Furthermore, we demonstrate decreased trabecular bone content of IGF-II and IGFBP-5 in these patients. However, we found no direct causal relationship between trabecular bone density and bone content of IGF-system components.     

Matrix in cartilage and bone development: current views on the function and regulation of major organic components

Study of the growth and development of cartilage and bone has been difficult because the structure of the tissues makes biological experiments hard to conduct. Recent advances in molecular biology have offered new possibilities for studying these processes. Many cartilage and bone specific cDNAs have been cloned and characterized and consequently used to localize the corresponding mRNAs in tissue sections. Developing cartilage and bone serve as a model for the study of extracellular matrix gene regulation during the proliferation, growth and differentiation of connective tissue cells. Normal skeletal growth and development are regulated by both systemic and local factors. The effects of many systemic hormones on bone metabolism have been studied extensively, but the pathways triggered by these hormones in the target cells are less well known. Recent evidence suggests that some growth factors, such as TGF-beta, IGFs and PDGF, act as local regulators of cartilage and bone metabolism. The different extracellular matrix components, e.g. collagens, are expressed differently in distinct cell types and developmental stages during cartilage and bone development. This model, therefore, facilitates the study of relations between the production of the various extracellular matrix components and the growth factors and the proto-oncogenes which may regulate them. Existing knowledge of the expression of major cartilage and bone components and their regulation during growth, differentiation and development is reviewed. An understanding of the normal growth and development of cartilage and bone is fundamental for elucidating the mechanisms underlying the various diseases -- both hereditary and acquired -- affecting the human skeleton.