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Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself. Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) α, TGFβ and CTGF (connective tissue growth factor). EGF and TGFα bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Theoretically, TGFα stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting. TGFβ(1) stimulates TGFβ receptors (TGFβRI and TGFβRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21(WAF1/CIP1). Although some NENs are inhibited by TGFβ(1), paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs. Therapeutic targeting of TGFβ(1) in NENs is therefore complicated by uncertainty of the effect of TGFβ(1) secretion on the direction of proliferative regulation. CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs. CTGF promotes growth in gastric and SI-NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin. CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs. In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified. [ABSTRACT FROM AUTHOR]

Abstract: Estrogen signaling in auditory and vestibular sensory epithelia is a newly emerging focus propelled by the role of estrogen signaling in many other proliferative systems. Understanding the pathways with which estrogen interacts can provide a means to identify how estrogen may modulate proliferative signaling in inner ear sensory epithelia. Reviewed herein are two signaling families, EGF and TGFß. Both pathways are involved in regulating proliferation of supporting cells in mature vestibular sensory epithelia and have well characterized interactions with estrogen signaling in other systems. It is becoming increasingly clear that elucidating the complexity of signaling in regeneration will be necessary for development of therapeutics that can initiate regeneration and prevent progression to a pathogenic state. [Copyright &y& Elsevier]

Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix in response to signaling molecules. MEK kinase 1 (MEKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase originally identified as an upstream activator for several MAPK pathways. During mouse embryogenesis, MEKK1 controls cell shape changes and formation of actin stress fibers that are required for sealing epidermis in the embryos in a process known as eyelid closure. MEKK1-null mice display eye-open at birth (EOB), a phenotype found also in mice impaired in activin, a subgroup of the transforming growth factor β (TGFβ) family, or in epidermal growth factor receptor (EGFR) or its ligand TGFα, or in transcription factor c-Jun. Molecular analyses have revealed at least two signaling mechanisms in the control of eyelid closure. One is originated from the activins and is transduced through MEKK1, leading to transcription-independent actin stress fiber formation and transcription-dependent keratinocyte migration. Another is the TGFα/EGFR signal that is transduced through a MEKK1-independent pathway to the activation of the ERK MAPK, which also leads to keratinocyte migration. c-Jun might serve as a connection between the two pathways. As embryonic eyelid closure is a specific morphogenetic process that is easily detectable, genetic mutant mice with EOB will be ideal models to understand the signaling mechanisms in the control of epithelial cell migration and the morphogenetic process of epithelial sheet movement. [Copyright &y& Elsevier]

Several growth factors (e.g., transforming growth factors beta and alpha, basic fibroblast growth factor), produced by hypothalamic astrocytes, participate in the control of hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. On this basis, we have hypothesized that steroid hormones, like estrogens and progestagens, influence the GnRH neurons by modulating in glial cells the synthesis and the release of these growth factors. Data reported here indicate that the expression of transforming growth factor beta 1 is modulated in hypothalamic astrocytes by a progesterone derivative (i.e., dihydroprogesterone), while estrogens modulate that of basic fibroblast growth factor. Moreover, it is interesting to highlight that the effect of estrogens on basic fibroblast growth factor is mediated by another growth factor (i.e., transforming growth factor alpha). Altogether, the present findings support the concept that steroid hormones and growth factors act in an integrated manner at the level of hypothalamic astrocytes, thus adding a further piece of knowledge in the understanding of the mechanisms controlling GnRH neurons. [ABSTRACT FROM AUTHOR]

The activation of transforming growth factor α (TGFcα)- erbB-1 and neuregulin- erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGFα with receptor phosphorylation, release of prostaglandin E[sub2] (PGE[sub2]), and a PGE[sub2]-dependent increase in the release of TGFβ[sub1], a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGFα on both PGE[sub2] and TGFβ[sub1] release. Time-lapse studies revealed that TGFα and TGFβ[sub1] have dramatically opposite effects on tanycyte plasticity. Whereas TGFα promotes tanycytic outgrowth, TGFβ[sub1] elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGFβ[sub1], suggesting that TGFα induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (>12 hr) exposure of tanycytes to TGFα resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGFβ[sub1] action, indicating that the retraction was attributable to TGFα-induced TGFβ[sub1] formation. These in vitro results identify tanycytes as targets. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Background: The objective of this study was to characterize the expression of transforming growth factor-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, transforming growth factor-beta/Type I-II transforming growth factor-beta receptors, stem cell factor, urokinase plasminogen activator, smooth muscle actin, CD34 and alpha-fetoprotein in human liver samples with (sub)massive necrosis of different etiology containing atypical ductular reaction. Methods: Their presence was studied by immunohistochemistry on paraffin-embedded tissue sections. Results: Transforming growth factor-alpha and -beta, hepatocyte growth factor and their receptors were demonstrated in the ductules; additionally stem cell factor and urokinase plasminogen activator were also expressed. The atypical ductules were surrounded by smooth muscle actin-positive activated stellate cells. Conclusion: These phenotypic similarities confirm that the atypical ductules in the human liver may be equivalent of oval cells in the rat liver, which are regarded as the progeny of stem cells. That is, the atypical ductular proliferation may correspond to a stem cell-fed regenerative process. [ABSTRACT FROM AUTHOR]

Peptide regulatory factors (PRFs) are critical components in the regulation of glomerular inflammatory response to immune injury and may also have a primary role in modulating intrinsic cell proliferation and matrix synthesis. Dysregulation of PRFs and glomerular infiltration with inflammatory, including mononuclear, cells occur in models of nephritis, but direct evidence for their role is not established in normal and diseased tissue in man. Using in situ hybridization techniques capable of detecting specific cellular messenger RNA we have evaluated normal human and IgA nephropathy diseased renal tissue for expression and location of PRF encoding mRNA. Permeabilized tissue was examined by autoradiography using S labelled-antisense, and -sense riboprobes for TGFα TGFβ, IGF 1, IL-4, and IL-6 encoding mRNA. TGFβ was constitutively expressed in normal glomerular mesangium, capillary loop, Bowman's capsule, and vascular endothelial and tubular cells, but was downregulated in IgA nephropathy tissue. In contrasting and distinct patterns, TGFα encoding mRNA was found in neither tissue, whereas IGF 1 mRNA was expressed in normal and also in diseased tissue. IGF 1 mRNA activity was intense within tubular cell cytoplasm in normals, with similar characteristics in IgA nephropathy. Cytokines IL-4 and IL-6 mRNAs were absent in normals, with IL-4 detectable throughout renal substance in disease; IL-6 gene transcription was intense in glomerular and vascular endothelial sites in IgA nephropathy. These findings implicate selective gene induction and suppression in disease, suggesting functional downregulation of glomerular TGFβ, coincident with autocrine functions for IL-6 and IL-4 in the pathogenesis of IgA-related nephropathy. [ABSTRACT FROM PUBLISHER]