scholarly journals Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies

2015 ◽  
Vol 2015 ◽  
pp. 1-24 ◽  
Author(s):  
Varsha P. Brahmkhatri ◽  
Chinmayi Prasanna ◽  
Hanudatta S. Atreya
Keyword(s):  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Cancer Therapies ◽  
Igf Binding Proteins ◽  
Growth And Survival ◽  
Igf System ◽  
Igf Receptors ◽  
Igf Binding ◽  
Promote Cell Cycle Progression

Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.

Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors

1996 ◽  
Vol 76 (4) ◽  
pp. 1005-1026 ◽  
Author(s):  
C. E. Stewart ◽  
P. Rotwein
Keyword(s):  
Growth Factors ◽  
Molecular Genetic ◽  
Igf Binding Proteins ◽  
Surface Receptors ◽  
Igf System ◽  
New Information ◽  
Igf Receptors ◽  
Igf I ◽  
Igf Binding ◽  
Insulin Like Growth Factors

The insulin-like growth factors (IGFs), IGF-I and IGF-II, comprise a conserved pair of secreted proteins with diverse effects on growth, development, and metabolism. Insulin-like growth factor action is initiated upon binding to cell-surface receptors and is modulated through interactions with secreted IGF binding proteins (IGFBPs). The last decade has seen an explosion of new information about the physiological roles of the IGFs. In this review, we critically examine this information from biochemical, cell biological, and molecular genetic perspectives. We discuss the structures and functions of the two IGF receptors, outline the actions of the six IGFBPs, and summarize and interpret recent studies highlighting essential roles for components of the IGF system in the growth and development of the embryo and fetus, in tissue differentiation, in cell survival and proliferation, and in cancer. These results are discussed in the context of new opportunities for understanding the mechanisms of IGF action in multiple biological processes.

IGF-II, IGF-binding proteins and IGF receptors in pancreatic β-cell lines

1997 ◽  
Vol 152 (3) ◽  
pp. 455-464 ◽  
Author(s):  
L E L Katz ◽  
A Bhala ◽  
E Camron ◽  
S E Nunn ◽  
R L Hintz ◽  
...  
Keyword(s):  
Cell Lines ◽  
Binding Proteins ◽  
Conditioned Media ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Igf Binding Proteins ◽  
Igf Receptors ◽  
Igf I ◽  
Igf Binding ◽  
Hit Cells

The IGFs are mitogenic agents which are closely linked to regulatory processes in carbohydrate metabolism. Because limited information is available on the occurrence of the IGF system in the pancreatic β-cell milieu, we evaluated the presence of IGFs, IGF receptors, and IGF-binding proteins (IGFBPs) in the β-cell lines βTC3 and HIT T-15. Serum-free conditioned media (SFCM) from βTC3 cells contained IGF-II at concentrations greater than 100 ng/ml. High (15 kDa) and low (7·5 kDa) molecular weight IGF-II were detected both by column chromatography followed by RIA and by immunoblotting. GH (10–1000 ng/ml) conditioning of βTC3 cells stimulated IGF-II secretion in a dose-dependent manner. IGF-II mRNA was detected in βTC3 cells using Northern blots, and also showed a GH-dependent relationship. IGF-II peptide was detected in SFCM from HIT cells, albeit at lower concentrations. To evaluate the presence of IGF receptors in β-cell lines, affinity cross-linking studies were performed on βTC3 cells, demonstrating type I IGF receptors which bound iodinated IGF-II with high affinity, iodinated IGF-I with lesser affinity, and had minimal appreciable binding to iodinated insulin. Type II IGF receptors were not detected. SFCM from βTC3 and HIT cells was subjected to Western ligand blotting, which disclosed the presence of two major IGFBPs of 29 kDa and 24 kDa, characteristic of IGFBP-2 and IGFBP-4. The identity of the specific IGFBPs was confirmed by immunoprecipitation and Northern blotting. Varying the glucose concentration had no significant effect on the levels of IGFBPs, nor did preconditioning with GH, IGF-I, IGF-II, insulin, or glucagon. Levels of both IGFBPs in βTC3 cell-conditioned media increased in the presence of dexamethasone at concentrations of 10−6 m or greater. In summary, we present evidence that β-cell lines comprise an environment for GH and IGF action. We speculate that IGFs, their receptors and binding proteins function as a complex interactive system which regulates β-cell growth and function. Journal of Endocrinology (1997) 152, 455–464

scholarly journals Chromogranin A, Ki-67 index and IGF-related genes in patients with neuroendocrine tumors

2013 ◽  
Vol 2 (4) ◽  
pp. 172-177 ◽  
Author(s):  
R C S van Adrichem ◽  
L J Hofland ◽  
R A Feelders ◽  
M C De Martino ◽  
P M van Koetsveld ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Neuroendocrine Tumors ◽  
Chromogranin A ◽  
Insulin Receptors ◽  
Proliferation Index ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Igf Binding Proteins ◽  
Igf Receptors ◽  
Igf Binding

Chromogranin A (CgA) and the Ki-67 proliferation index are considered as important biochemical and pathological markers for clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP NETs), respectively. The IGF system has been suggested as an important regulator of GEP NET proliferation and differentiation. A possible relationship between serum CgA (sCgA), Ki-67 proliferation index, and expression of IGF-related genes in patients with GEP NETs has not been demonstrated yet. This study investigates the relationship between sCgA, the Ki-67 proliferation index, and the expression of IGF-related genes in GEP NET tissues and their relation with 5-year survival. Tumor and blood samples from 22 GEP NET patients were studied. Tumoral mRNA expression of IGF-related genes (IGFs: IGF1, IGF2; IGF receptors: IGF1R, IGF2R; insulin receptors: subtype A (IR-A) and B (IR-B); IGF-binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, and IGFBP6) was measured using quantitative RT-PCR. Ki-67 proliferation index was determined using immunohistochemistry. sCgA was measured with ELISA. Five-year survival in patients with nonelevated sCgA (n=11) was 91 vs 46% in patients with elevated sCgA (n=11) (P=0.006). IR-A mRNA expression was significantly higher in tumors obtained from patients with elevated sCgA than in those from patients with nonelevated sCgA (6.42±2.08 vs 2.60±0.40; P=0.04). This data suggests that sCgA correlates well with 5-year survival of GEP NET patients, and that IR-A mRNA expression correlates well with tumor mass in GEP NET patients.

scholarly journals Endothelial cells and the IGF system

2014 ◽  
Vol 54 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Leon A Bach
Keyword(s):  
Endothelial Cells ◽  
Vascular Tone ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Tube Formation ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Igf Binding ◽  
And Function ◽  
Cell Phenotypes

Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.

scholarly journals The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system

2001 ◽  
Vol 170 (1) ◽  
pp. 63-70 ◽  
Author(s):  
YR Boisclair ◽  
RP Rhoads ◽  
I Ueki ◽  
J Wang ◽  
GT Ooi
Keyword(s):  
Current Knowledge ◽  
Biological Fluids ◽  
Limited Attention ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Binary Complexes ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Acid Labile

The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.

scholarly journals The growth hormone axis and insulin-like growth factors

2005 ◽  
Vol 58 (11-12) ◽  
pp. 558-562 ◽  
Author(s):  
Tatjana Radosavljevic ◽  
Vera Todorovic ◽  
Danijela Vucevic ◽  
Branka Sikic
Keyword(s):  
Growth Factors ◽  
Critical Role ◽  
The Body ◽  
Alternative View ◽  
Igf Binding Proteins ◽  
Peripheral Tissues ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Insulin Like Growth Factors

Introduction Growth is regulated by the interaction of environmental signals with endogenous neuroendocrine responses to the genetic programs that determine the body plan. The insulin-like growth factors (IGFs) are integral components of multiple systems controlling both growth and metabolism. The IGF system The IGF system is thought to be more complex than other endocrine systems, as genes for six IGF-binding proteins (IGFBPs) have been identified so far. The IGFs play a critical role in both cell cycle control and apoptosis, two functions involved in regulation of tumorigenesis. Insulin-like growth factor-I (IGF-I) is essential for normal growth. Confirmation of the significance of IGF-I in human physiology was obtained by the discovery of a patient with intrauterine growth retardation and postnatal growth failure associated with a mutation in the IGF-1 gene. Stages of evolution of the somatomedin hypothesis The original somatomedin hypothesis postulated that somatic growth was regulated by growth hormone's (GH's) stimulation of hepatic IGF-1 production, with IGF-1 acting in an endocrine fashion to promote growth. The dual effectors theory proposed an alternative view, involving direct effects by GH on peripheral tissues not mediated by IGF-1 and GH-stimulated local IGF-1 production for autocrine/paracrine action. It is now clear that G H stimulates the formation of ternary IGF binding complex, which stabilizes IGF-I in the serum.

Acute response of IGF-I and IGF binding proteins induced by thermal injury

2000 ◽  
Vol 278 (6) ◽  
pp. E1087-E1096 ◽  
Author(s):  
Charles H. Lang ◽  
Xiaoli Liu ◽  
Gerald J. Nystrom ◽  
Robert A. Frost
Keyword(s):  
Plasma Concentration ◽  
Binding Proteins ◽  
Thermal Injury ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Significant Difference ◽  
Mrna Transcripts ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Previous studies demonstrate that thermal injury decreases circulating levels of insulin growth factor I (IGF-I) and alters the plasma concentration of several IGF binding proteins (IGFBP), but the mechanisms for these alterations have not been elucidated. In the current study, a 30% total body surface area full-thickness scald burn was produced in anesthetized rats, and animals were studied 24 h later. The plasma concentration of both total and free IGF-I was decreased (38 and 65%, respectively) in burn rats compared with values from time-matched control animals. Thermal injury decreased the IGF-I peptide content in liver ∼40%, as well as in fast-twitch skeletal muscle (56–69%) and heart (28%). In contrast, IGF-I content in kidney was elevated by 36% in burn rats. Northern blot analysis of liver indicated that burn decreased the expression of small (1.7- and 0.9- to 1.2-kb) IGF-I mRNA transcripts but increased the expression of the 7.5-kb transcript. In contrast, there was a coordinate decrease in all IGF-I mRNA transcripts in muscle and kidney of ∼30%. For liver, muscle, and kidney, there was no significant difference in the expression of growth hormone receptor mRNA between control and burn rats. Thermal injury increased plasma IGFBP-1 levels, and this change was associated with increased IGFBP-1 mRNA in both liver and kidney. IGFBP-3 levels in plasma were concomitantly decreased by burn injury. This change was associated with a reduction in IGFBP-3 mRNA in liver but an increased expression of IGFBP-3 in kidney and muscle. Thermal injury also decreased the concentration of the acid-labile subunit (ALS) in plasma and ALS mRNA expression in liver. Finally, hepatic expression of IGFBP-related peptide-1 was increased twofold in liver but was unchanged in kidney or muscle of burn rats. These results characterize burn-induced changes in various components of the IGF system in select tissues and thereby provide potential mechanisms for alterations in the circulating IGF system and for changes in tissue metabolism.

scholarly journals Transport of IGF-I across epithelial cell monolayers

1999 ◽  
Vol 162 (3) ◽  
pp. 361-369 ◽  
Author(s):  
SE Bastian ◽  
PE Walton ◽  
FJ Ballard ◽  
DA Belford
Keyword(s):  
Epithelial Cell ◽  
Cell Lines ◽  
Igf Binding Proteins ◽  
Cell Monolayers ◽  
High Affinity ◽  
Igf Receptors ◽  
Igf I ◽  
Mdbk Cells ◽  
Igf Binding ◽  
Epithelial Cell Monolayers

Epithelial cells line the lumens of organs including the gastrointestinal tract, kidney tubules and respiratory airways, where they regulate the transport of electrolytes and the movement of macromolecules. The current study aimed to investigate the transport of IGF-I across epithelial cell barriers. Epithelial cell lines derived from gut (IEC-6), kidney (MDBK) and lung (Mv1Lu) were shown to possess high-affinity, functional receptors for IGF-I and formed tight junctions in monolayer culture. To investigate the transport of IGF-I, the three cell lines were grown on microporous filters in a bi-chamber system. In comparison with filters without cells, IEC-6 and Mv1Lu epithelial cell monolayers restricted the passage of (125)I-IGF-I and [(3)H]inulin, whereas the MDBK cells virtually occluded any passage of these molecules. Transport of (125)I-IGF-I across the epithelial cell monolayers was significantly less than that of [(3)H]inulin, suggesting that the binding of (125)I-IGF-I to high-affinity IGF receptors or IGF-binding proteins retarded its transport. Moreover, (125)I-IGF-I transport was not inhibited by the presence of excess unlabelled IGF-I. Our findings provide evidence for the restricted diffusion of intact, free IGF-I across gut, kidney and lung epithelial cell monolayers via a paracellular or low-affinity transcellular pathway.

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