Hormones and growth factors involved in supplying offspring: Insights from fish to mammals.

There is increasing evidence that growth factors modulate folliculogenesis. However their precise role in the processes of follicular growth, differentiation and atresia is still unknown. Growth factors belong to complex systems, including all the factors structurally and functionally related, their receptor(s) and, in most cases, binding proteins or proteoglycans. In this review, the insulin-like growth factor (IGF) system is presented as a paradigm for the study of other growth factor systems in the ovary. IGFs are probably positive regulators of follicular development, as they enhance both proliferation and differentiation and amplify the action of gonadotrophins on follicular cells. In the ovaries of most mammals, there is little or no change in intrafollicular IGF concentrations during terminal follicular growth and atresia. By contrast, the concentrations of IGF-binding proteins < 40 kDa (mainly IGFBP-2, -4 and -5) decrease markedly during terminal follicular growth, but increase in atretic follicles. These variations could result from both changes in expression of these IGFBPs by follicular cells and in local degradation by gonadotrophin-induced specific protease(s). Experiments in vitro showed that these IGFBPs, present in a soluble form in follicular fluid, could play an important role by sequestrating the IGFs and decreasing their bioavailability. More generally, biological actions of growth factors critically depend on their bioavailability in the vicinity of the cell, resulting from the concentrations of the factors themselves, their binding proteins and the ability of specific proteases to degrade binding proteins or to cleave latent forms of growth factors. These mechanisms and their control by gonadotrophins throughout follicular development have now to be investigated for the different growth factor systems.

Growth factor regulation of fracture repair.

Activation of growth factor receptors in pancreatic cancer

Ovarian Electrocauterization Changes the Level of Insulin-Like Growth Factor-I in Clomiphene Citrate-Resistant Patients with Polycystic Ovary Syndrome

ContentsThis review will present a characterization of basic molecular processes in the mammalian oviduct. Oviducts of the cow (Bos taurus) were examined during the various cycle stages using a combination of cell biology‐ and molecular‐biology techniques [reverse transcriptase polymerase chain reaction (RT‐PCR), RNase protection assay (RPA), immunohistology, radio‐immunoassay (RIA), receptor‐assay, cell culture]. In detail the oviductal expression of the following components was analysed: fibroblast (FGF) and vascular‐endothelial (VEGF) growth factor systems; extracellular matrix (ECM) enzymes such as plasminogenactivator (PA) and matrixmetalloproteases (MMP), adrenergic receptors (α2 and β2 AdR) and an anti‐oxidative protein (glutathionperoxidase = GPx). A specific cycle‐dependant and local regulation of the expression could be demonstrated, not only for growth factors such as FGF1 and VEGF but also for ECM components. Remarkable progesterone‐dependent increases of the β2 adrenoceptor concentrations were found in the oviductal epithelium. New observations showed the presence of antioxidative enzymes (GPx) in the bovine oviduct possibly interacting with the gametes. Obviously, a network of local factors seems to influence the function of the oviduct, controlled by peripheral hormones. Cycle–dependent interactions between the growth factor, ECM and adrenergic systems will create the optimal environment for fertilization and early embryo development in the mammalian oviduct.

Insulin-like growth factors (IGF) system plays an important role in regulating growth and development of children. The change of this system is closely related to growth restriction caused by various diseases. This article reviews the research progress on how IGF system affects growth.

Chapter 18 Modeling of Growth Factor-Receptor Systems: From Molecular-Level Protein Interaction Networks to Whole-Body Compartment Models

Various growth factors have been proposed to be players in different areas of diabetes mellitus including a possible relationship to the characteristic changes in metabolism and development of complications. In particular, growth hormone (GH) and insulin-like growth factors (IGFs) system have a long and distinguished history with relation both to the diabetic metabolic aberration and the pathogenesis of diabetic angiopathy. The published evidence covering this area has recently been reviewed [1–3]. Further, substantial evidence has suggested that some growth factors (i.e. GH and IGFs, epidermal growth factor (EGF), transforming growth factor β (TGF-β), platelet derived growth factor (PDGF), tumor necrosis factor a (TNF-α) and fibroblastic growth factors (FGFs)) have conceivable effects on the development of renal complications in diabetes as reviewed in The Kidney and Hypertension in Diabetes Mellitus, 2th Edition, 1994 [4]. The present review is an update of the topic with emphasis on three of the above mentioned growth factor systems and a new promising candidate, i.e. vascular endothelial growth factor (VEGF). The first part of the review presents an update for a definite role of the GH/IGF system in the pathogenesis of the renal changes in experimental diabetes with focus on the renoprotective effects of long-acting somatostatin analogues and GH-receptor antagonists. In the second and third part, an update of the literature suggesting a causal role for EGF and TGF-β in the patogenesis of diabetic renal changes is presented and in the fourth part the new evidence of VEGF being involved in the development of diabetic kidney disease is given.

THE DEVELOPMENT, growth, and maintenance of a functional skeleton relies on the existence of several different types of chondrocytes with markedly different fates. The articular chondrocytes on the surface of joints are expected to persist throughout life, producing extracellular matrix components which provide a cushion to distribute load on bone at joints. In contrast, it is the changing dynamics of the underlying cartilage at the epiphyseal growth plate that permits a very different function: growth and development. Chondrocytes of this region undergo a series of changes including hypertrophy, release of extracellular matrix vesicles, and alterations in production of extracellular matrix proteins, prior to mineralization and replacement by bone. As chondrocytes progress toward terminal differentiation, morphological, and biosynthetic changes occur. Proliferating chondrocytes exit the cell cycle and become flattened before fully maturing into round, hypertrophic chondrocytes which secrete and organize a different extracellular matrix, characterized by high levels of alkaline phosphatase (ALP), diminished levels of collagens type II and IX, and production of a new hypertrophic chondrocytespecific product, type X collagen. In addition to normal bone formation during development of the skeleton, this process of endochondral ossification has also been implicated in fracture repair and such pathologic processes as osteoarthritis and ectopic bone formation. The fundamental importance of chondrocyte maturation in the growth, development, and repair of the skeleton has led to intense investigation of the growth factors that regulate terminal differentiation of chondrocytes. Although several growth factors have been indentified which regulate chondrocyte maturation, it remains unclear how these factors interact to coordinate the process leading to bone elongation and endochondral ossification. In this issue, Grismud and colleagues propose a role for bone morphogenetic protein-6 (BMP-6) as a positive regulator of chondrocyte maturation. Their report also provides insight into how parathyroid hormone-related protein (PTHrP) and indian hedgehog, other growth factors known to modulate chondrocyte hypertrophy, may interact with BMP-6 in the growth plate. BMPs belong to the transforming growth factor-b (TGFb) superfamily of secreted growth and differentiation polypeptides, which also includes activins, growth and differentiation factors, and Mullerian inhibiting substance. For over 30 years, it has been known that BMPs are capable of inducing the formation of new cartilage and bone when implanted extraskeletally. However, it was not until 1988 that three of the proteins involved (BMP2–4) were cloned. Although their name stresses their critical impact on the skeletal system, more than 20 members of the BMP family have been identified and determined to have a broader biological impact than just skeletogenesis. This impact includes establishment of basic embryonic patterning and growth and differentiation of nearly all body systems including the cardiovascular, gastrointestinal, respiratory, nervous, and urogenital systems and the integument (see review by Hogan). As their name implies, most BMPs can initiate new cartilage and bone formation in a cascade of events reminiscent of endochondral bone formation. BMP-2, BMP-4, BMP-5, and BMP-7 have all been shown to possess the ability to promote bone formation in vivo. Additional evidence with cultured cells also point to considerable overlap in BMP function; recombinant BMP-2, BMP-4, BMP-6, and BMP-7 have all been shown to induce both hypertrophy in cultured chondrocytes and osteogenesis from mesenchymal stem cells. However, information derived from BMP localization studies and null mutations in mice suggests more specific roles for individual BMPs in normal development. The temporal and spatial patterns of expression of BMPs in embryonic mouse forelimbs support roles for BMP-2, BMP-4, BMP-6, and BMP-7 in skeletal formation, and multiple BMPs, including BMP-2, BMP-4, BMP-6, and BMP-7, are produced by chondrocytes undergoing endochondral ossification. Recent detailed analysis of expression patterns for BMPs in the embryonic mouse humerus by Solloway et al. show that BMP-7 is expressed in both proliferating chondrocytes and the perichondrum, BMP-4 is found in chondrocytes of the transition zone immediately adjacent to the mature hypertrophic chondro-

The plasminogen-related family of growth factors includes the hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), both of which normally mediate a variety of cellular behaviors including proliferation, survival, and migration. A major contributor to the formation and persistence of various cancers is the dysregulation of these growth factor systems. Overexpression of the HGF receptor, c-Met, is common in many cancers including pancreatic cancer, and is associated with poor prognosis. Dysregulation of this system often leads to tumorigenesis and induction of various malignant phenotypes including increased proliferation, survival, migration, and invasion. In order to activate c-Met, HGF must first undergo an activation step in which it forms an HGF homodimer. Small molecule antagonists with homology to a putative “hinge” region within the HGF sequence have been developed that bind to HGF and allosterically block dimerization, therefore inhibiting c-Met signaling. Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] has previously been shown to inhibit HGF dimerization and HGF-dependent c-Met activation. We have assessed the ability of Norleual to block HGF dimerization and activation of c-Met within pancreatic cancer cells. Similar to the HGF/c-Met system, over-activation of the closely related MSP/Ron (MSP receptor) growth factor system has been identified as a critical contributor to pancreatic cancer progression. Due to overall high sequence homology between HGF and MSP, including the putative “hinge” region, we have hypothesized that MSP must also dimerize in order to efficiently activate the Ron receptor, and that this activation step can be targeted by “hinge” region homologs. Our results indicate that MSP naturally forms dimers and incubation with Norleual and similar “hinge” region antagonists inhibits dimerization. Further, we have demonstrated that MSP dimerization may be biologically significant and inhibition of dimerization suppresses MSP-dependent cell signaling and cell behaviors. The ultimate goal of this work is to develop a dual inhibitor capable of suppressing both the HGF and MSP growth factor systems, and further assess the therapeutic potential of these inhibitors for treatment of pancreatic cancer. Citation Format: Kevin J. Church, Leen Kawas, Joseph Harding, Malte Lang, Michelle McMicheal. Development of allosteric regulators of the dimerization domains of the plasminogen-related growth factor family for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2708. doi:10.1158/1538-7445.AM2014-2708

Neurotrophic growth factors were originally characterized for their support in neuronal differentiation, outgrowth, and survival during development. However, it has been acknowledged that they also play a vital role in the adult brain. Abnormalities in growth factors have been implicated in a variety of neurological and psychiatric disorders, including alcohol use disorder (AUD). This work focuses on the interaction between alcohol and growth factors. We review literature suggesting that several growth factors play a unique role in the regulation of alcohol consumption, and that breakdown in these growth factor systems is linked to the development of AUD. Specifically, we focus on the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), and insulin growth factor 1 (IGF-1). We also review the literature on the potential role of midkine (MDK) and pleiotrophin (PTN) and their receptor, anaplastic lymphoma kinase (ALK), in AUD. We show that alcohol alters the expression of these growth factors or their receptors in brain regions previously implicated in addiction, and that manipulations on these growth factors and their downstream signaling can affect alcohol-drinking behaviors in animal models. We conclude that there is a need for translational and clinical research to assess the therapeutic potential of new pharmacotherapies targeting these systems.

Quantitation of the mRNA expression of the epidermal growth factor system: Selective induction of heparin-binding epidermal growth factor–like growth factor and amphiregulin expression by growth factor stimulation of prostate stromal cells

To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200-300% of the normal level 3-5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-alpha (TGF-alpha), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-beta1, TGF-beta type II receptor, hepatocyte growth factor (HGF), and c-MET/HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3-5 days after androgen replacement. The second increase was evident in TGF-alpha, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates.

Various growth factors have been proposed to be players in different areas of diabetes mellitus including a possible relationship to the characteristic changes in metabolism and development of complications. In particular, growth hormone (GH) and insulin-like growth factors (IGFs) system have a long and distinguished history with relation both to the diabetic metabolic aberration and the pathogenesis of diabetic angiopathy. The published evidence covering this area has recently been reviewed [1–3]. Further, substantial evidence has suggested that some growth factors (i.e. GH and IGFs, epidermal growth factor (EGF), transforming growth factor β (TGF-s), platelet derived growth factor (PDGF), tumor necrosis factor a (TNF-α) and fibroblastic growth factors (FGFs)) have conceivable effects on the development of renal complications in diabetes as reviewed in The Kidney and Hypertension in Diabetes Mellitus, Second Edition, 1994 [4]. The present review is an update of the topic with emphasis on three of the above mentioned growth factor systems. The first part of the review presents an update for a definite role of the GH/IGF system in the pathogenesis of the renal changes in experimental diabetes with focus on the renoprotective effects of long-acting somatostatin analogues and GH-receptor antagonists. In the second and third part, an update of the literature is presented suggesting a causal role for EGF and TGF-β in the development of diabetic kidney disease.

To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200–300% of the normal level 3–5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-α (TGF-α), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-β1, TGF-β type II receptor, hepatocyte growth factor (HGF), and c-MET/HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3–5 days after androgen replacement. The second increase was evident in TGF-α, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates. © 1996 Wiley-Liss, Inc.