Insulin-like growth factor-I (IGF-I) is a mitogen for prostate epithelial cells. To investigate associations between plasma IGF levels and prostate cancer risk, a nested case-control study within the Physicians' Health Study was conducted on prospectively collected plasma from 152 cases and 152 controls. A strong positive association was observed between IGF-I levels and prostate cancer risk. Men in the highest quartile of IGF-I levels had a relative risk of 4.3 (95 percent confidence interval 1.8 to 10.6) compared with men in the lowest quartile. This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment.

https://science.sciencemag.org/content/sci/279/5350/563.full.pdf

Plasma Insulin-Like Growth Factor-I and Prostate Cancer Risk: A Prospective Study

In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction with cell or matrix components may concentrate IGFs near their receptor, enhancing IGF activity. IGF receptor-independent IGFBP actions are also increasingly recognized. IGFBP-1 interacts with alpha(5)beta(1) integrin, influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl-terminal basic motifs incorporating heparin-binding and additional basic residues that interact with the cell surface and matrix, the nuclear transporter importin-beta, and other proteins. Serine/threonine kinase receptors are proposed for IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell surface IGFBP-interacting proteins are uncharacterized as functional receptors. However, IGFBP-3 binds and modulates the retinoid X receptor-alpha, interacts with TGFbeta signaling through Smad proteins, and influences other signaling pathways. These interactions can modulate cell cycle and apoptosis. Because IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases.

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Cellular actions of the insulin-like growth factor binding proteins.

The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.

/pdf/role-of-the-insulin-like-growth-factor-family-in-cancer-550yl3popq.pdf

Role of the insulin-like growth factor family in cancer development and progression

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.

/pdf/systemic-complications-of-acromegaly-epidemiology-48hlt1tw8j.pdf

Systemic complications of acromegaly: epidemiology, pathogenesis, and management.

I. Introduction II. Characteristics of the IGFBPs III. Target Cell Actions of the IGFBPs A. To modulate IGF actions B. To facilitate storage of IGFs in extracellular matrices C. To exert IGF-independent effects IV. IGF-IGFBP Complexes in Biological Fluids A. Serum B. Milk C. Urine D. Cerebrospinal fluid (CSF) E. Follicular fluid F. Amniotic fluid G. Lymph H. Seminal fluid I. Other biological fluids V. Assays for Circulating Levels of IGFBP A. Western ligand blotting B. Western immunoblotting C. RIA D. Immunoradiometric assay (IRMA) VI. Relative Distribution of IGFBPs in Serum VII. Regulation of Serum IGFBPs A. Physiological conditions B. Development and aging C. Hormonal effects: mechanisms D. Pathological conditions VIII. IGFBP Proteases in Circulation A. Proteases under normal conditions B. Pregnancy-associated proteases C. Proteases under catabolic and disease states IX. Endocrine Functions of IGFBPs in Serum A. To prevent insulin-like effects B. To increase the half-lives of IGFs C. To control the tra...

/pdf/insulin-like-growth-factor-binding-proteins-in-serum-and-2iwbeacfvt.pdf

Insulin-Like Growth Factor-Binding Proteins in Serum and Other Biological Fluids: Regulation and Functions

Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. Cell surface binding and growth inhibition.

The cDNAs encoding three major insulin-like growth factor-binding proteins (IGFBPs) have been cloned and sequenced. We have examined, by Western ligand blotting, the profiles of these binding proteins in human female serum in the normal menstrual cycle, throughout pregnancy, and during the postpartum period. There was no change in the serum profile of any of the binding proteins in early pregnancy compared to that in the secretory phase of the menstrual cycle. However, there was a marked decrease in circulating levels of the main serum IGFBP, IGFBP-3, after 6 weeks of gestation, continuing progressively to term and returning to nonpregnant levels by 5 days postpartum. IGFBP-2 decreased steadily throughout gestation. In contrast, IGFBP-1 levels were found to rise by the second trimester. Endoglycosidase-F digestion did not enhance detection of IGFBP-3 by ligand blotting. Immunoprecipitations with two separate antibodies against IGFBP-3 and IGFBP-2, followed by Western ligand blotting, confirmed the marked decrease in IGFBP-3 levels after 6 weeks of gestation and the more gradual decrease in IGFBP-2. In contrast, immunoprecipitations with IGFBP-1 monoclonal antibodies confirmed the increase in IGFBP-1 during gestation. Endogenous serum IGFs were separated from serum IGFBPs by acid chromatography, and an 80% decrease in total IGF-binding activity in the IGFBP fraction of chromatographed pregnancy vs. nonpregnancy serum was detected by charcoal absorption assay. Furthermore, immunoprecipitations of IGF affinity cross-linked IGFBP fractions with IGFBP-3-specific antiserum confirmed a marked diminution of IGFBP-3 in pregnancy compared to nonpregnancy serum, and revealed, only in pregnancy serum, the concomitant appearance of a band with a mol wt of 34K and three less intense bands with mol wt between 20-26K on sodium dodecyl sulfate gels. Incubation of nonpregnancy serum with 6-week pregnancy serum at 37 C for 5 h, followed by Western ligand blotting, showed only a slight reduction in the amount of IGFBP-3 in the mixture compared to that in controls. However, incubation of term pregnancy with nonpregnancy serum at 37 C for 5 h revealed a marked reduction of IGFBP-3 in the mixture. When iodinated recombinant IGFBP-3 was incubated with term pregnancy serum under the same conditions, the appearance of a 29K protein was identified by gel electrophoresis and autoradiography, along with three less intense bands with mol wt between 17-22K.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: effects of a pregnancy-associated serum protease activity.

Insulin-like growth factors (IGFs) are potent mitogens that bind with high affinity and specificity to IGF receptors and IGF-binding proteins (IGFBPs). We studied the roles of these three groups of proteins in prostate epithelial cells (PEC) in primary culture grown under serum-free conditions. Affinity cross-linking of IGF-I and IGF-II to crude membranes prepared from PEC revealed an abundance of type 1 IGF receptors and no evidence of type 2 IGF receptors. Western ligand blots of conditioned media (CM) from PEC demonstrated the presence of two specific IGFBP bands similar to those previously demonstrated in seminal plasma, with approximate mol wt of 31 and 24 kDa. The 31-kDa band was immunoprecipitable with an antibody to IGFBP-2, and neither band could be deglycosylated with endoglycosidase-F. Northern blot analysis of poly(A)+ RNA prepared from PEC with cDNAs for hIGFBP-1, -2, and -3 documented the expression of mRNA for hIGFBP-2 only. Modifications of the serum-free conditions of PEC did not signific...

Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells.

Publisher Summary This chapter provides an overview of insulin-like growth factor-binding proteins (IGF-BP). The insulin-like growth factors (IGFs)—or somatomedins—constitute a family of growth hormone (GH)-dependent peptides with both anabolic and mitogenic activities for a wide variety of tissues and cell lines. IGF-I and -II are characterized by a striking structural homology with human proinsulin. The human gene for IGF-II is located on the short arm of chromosome 11 in close proximity to the gene for insulin and spans over 30 kb of DNA. This gene is composed of at least eight exons. The preprohormone consists of a 24-amino-acid signal peptide, a 67-amino-acid mature peptide, and a carboxy-terminal peptide of 89 amino acids. Significant diversity exists in the 5'-untranslated regions, where different mRNA species arise as a result of distinct promoters and alternative RNA splicing. Both IGF-I and -II are synthesized in a wide variety of tissues. The close relationship between insulin and IGF-I receptors is not surprising, given the binding affinities and structural similarities of the two receptors. Unlike the insulin and IGF-I receptors, the type 2 IGF receptor is characterized by a long extracellular domain, containing 15 repeat sequences of approximately 150 residues, a 23-residue transmembrane domain, and a small 164-residue cytoplasmic domain. No homology exists between the type 2 IGF receptor and the insulin or type 1 receptor. The initial characterization of IGF-BPs was done by gel filtration chromatography. The chapter discusses radioreceptor assays, affinity labeling, western ligand blotting, and immune-precipitation among other methods of detection.

Insulinlike growth factor-binding proteins.

An assay for assessing the proteolysis of IGFBP-3 by a biological fluid or protein has been developed using 125I hIGFBP-3 recombinantly derived from Escherichia coli as a substrate indicator. The labelled substrate is incubated at 37° in the presence of the agent being tested and proteolysis is visualized by SDS-PAGE and autoradiography. The assay showed that the pregnancy associtatcd protease is Ca++ dependent. The substrate is also proteolyed by rat and mouse pregnancy sera, making the assay applicable to studies in those animal systems.

George Lamson

Papers

Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. Cell surface binding and growth inhibition.

Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: effects of a pregnancy-associated serum protease activity.

Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells.

Insulinlike growth factor-binding proteins.

A simple assay for proteolysis of IGFBP-3