scispace - formally typeset
Search or ask a question

Showing papers on "Growth factor receptor inhibitor published in 1993"


Journal ArticleDOI
TL;DR: It is demonstrated that human foreskin fibroblasts produce high levels of CTGF mRNA and protein after activation with transforming growth factor beta (TGF-beta) but not other growth factors including PDGF, epidermal growth factor, and basic fibroblast growth factor.
Abstract: Connective tissue growth factor (CTGF) is a cysteine-rich peptide that exhibits platelet-derived growth factor (PDGF)-like biological and immunological activities. CTGF is a member of a family of peptides that include serum-induced immediate early gene products, a v-src-induced peptide, and a putative avian transforming gene, nov. In the present study, we demonstrate that human foreskin fibroblasts produce high levels of CTGF mRNA and protein after activation with transforming growth factor beta (TGF-beta) but not other growth factors including PDGF, epidermal growth factor, and basic fibroblast growth factor. Because of the high level selective induction of CTGF by TGF-beta, it appears that CTGF is a major autocrine growth factor produced by TGF-beta-treated human skin fibroblasts. Cycloheximide did not block the large TGF-beta stimulation of CTGF gene expression, indicating that it is directly regulated by TGF-beta. Similar regulatory mechanisms appear to function in vivo during wound repair where there is a coordinate expression of TGF-beta 1 before CTGF in regenerating tissue, suggesting a cascade process for control of tissue regeneration and repair.

714 citations


Journal ArticleDOI
TL;DR: Part I of this two-part series presents an overview of the biochemical properties of five families of peptide growth factors that are thought to be involved in wound healing: epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta), platelet-derived growthFactor (PDGF), insulin-like growth factors (IGF), and fibroblast growth factor(FGF).
Abstract: Wound healing is a complex biologic process that involves chemotaxis and division of cells, neovascularization, synthesis of extracellular matrix proteins, and remodeling of scar. Peptide growth factors have been shown to regulate many of these processes in vitro, leading to the hypothesis that peptide growth factors also regulate important phases of wound healing in vivo. Part I of this two-part series presents an overview of the biochemical properties of five families of peptide growth factors that are thought to be involved in wound healing: epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and fibroblast growth factor (FGF).

665 citations



Journal Article
TL;DR: Findings suggest that coexpression of EGFR and its ligands may contribute to the aggressiveness of human pancreatic cancer.
Abstract: Immunohistochemical analysis for the epidermal growth factor receptor (EGFR), EGF and transforming growth factor-alpha (TGF-alpha) was performed in 87 human pancreatic carcinomas. Expression frequencies for EGFR, EGF, and TGF-alpha were 43%, 46% and 54%, respectively. Coexpression of the receptor and at least one of its ligands occurred in 38% of the tumors, and correlated with large tumor size, advanced clinical staging, and decreased survival period. In situ hybridization revealed that the respective mRNAs were also overexpressed in the carcinomas. These findings suggest that coexpression of EGFR and its ligands may contribute to the aggressiveness of human pancreatic cancer.

421 citations


Journal Article
TL;DR: It is reported that both urokinase-type plasminogen activator and tissue-type Plasminogens activator can cleave single-chain hepatocyte growth factor, generating two- Chain hepatocytes growth factor.
Abstract: Hepatocyte growth factor, also known as scatter factor, is a complete mitogen for hepatocytes that bears sequence and structural homology with plasminogen. Because it exists in both a mitogenically inactive single-chain form and an active two-chain form, we were interested in determining whether plasminogen activators could properly cleave single-chain hepatocyte growth factor to generate active two-chain hepatocyte growth factor. Herein we report that both urokinase-type plasminogen activator and tissue-type plasminogen activator can cleave single-chain hepatocyte growth factor, generating two-chain hepatocyte growth factor. When equal quantities of plasminogen activator-treated and activator-untreated hepatocyte growth factor are compared in serum-free in vitro bioassays, the treated hepatocyte growth factor is mitotically more active. Also, urokinase-type plasminogen activator was inactive against hepatocyte growth factor molecules with a mutated cleavage site. This suggests that urokinase-type and tissue-type plasminogen activator may be natural biological regulators of hepatocyte growth factor. Because the active form of hepatocyte growth factor is a powerful stimulator of DNA synthesis and cell motility, these findings may be relevant in understanding the role of plasminogen activators in the biology of cancer invasion and metastasis.

392 citations


Journal ArticleDOI
24 Sep 1993-Science
TL;DR: Activation of this factor was independent of the normal functioning of Ras, and required the major sites for autophosphorylation on the EGF receptor that bind Src homology region 2 domain-containing proteins implicated in Ras activation.
Abstract: Interferons induce transcriptional activation through tyrosine phosphorylation of the latent, cytoplasmic transcription factor interferon-stimulated gene factor-3 (ISGF-3). Growth factors and cytokines were found to use a similar pathway: The 91-kilodalton subunit of ISGF-3 was activated and tyrosine phosphorylated in response to epidermal growth factor (EGF), platelet-derived growth factor, and colony stimulating factor-1. The tyrosine phosphorylated factor acquired DNA binding activity and accumulated in nuclei. Activation required the major sites for autophosphorylation on the EGF receptor that bind Src homology region 2 domain-containing proteins implicated in Ras activation. However, activation of this factor was independent of the normal functioning of Ras.

327 citations


Journal ArticleDOI
04 Mar 1993-Nature
TL;DR: The activation by EGF of a DNA-binding protein in a cell-free system where activation of DNA binding requires ligand, receptor, ATP and phosphotyrosine–SH2 interactions is reported.
Abstract: GROWTH factors such as platelet-derived growth factor and epidermal growth factor (EGF) bind to and activate cell-surface receptors with intrinsic tyrosine kinase activities1. Receptor activation elicits multiple physiological changes in target cells, including alterations in gene expression2–4. Receptor tyrosine kinase signalling involves recruitment of proteins into a signalling complex through interactions between receptor autophosphorylation sites and the src-homology region-2 (SH2) domains on these signalling proteins5–9. Diverse signals can subsequently be generated, depending on the specific receptor and cell type2,10. How such signals are transmitted to the nucleus is poorly understood, but because the transcriptional activation of many genes by growth factors occurs in the absence of new protein synthesis4, one or more signals emanating from growth factor receptors must directly affect transcription factors. We report here the activation by EGF of a DNA-binding protein in a cell-free system where activation of DNA binding requires ligand, receptor, ATP and phosphotyrosine–SH2 interactions.

250 citations


Journal Article
TL;DR: The results indicate that these three cell lines grow by an autocrine loop in which the overproduced IGF-1 activates its receptor and interference with the activation of the receptor leads to cessation of growth.
Abstract: We have investigated three prostatic cancer cell lines, PC-3, DU-145, and LNCa.FGC, and found that all three cell lines can grow in serum-free medium without the addition of exogenous growth factors. All three cell lines produce substantial amounts of insulin-like growth factor 1 (IGF-1) that is secreted in the medium and they all display constitutively autophosphorylated IGF-1 receptors; two of the cell lines overexpress IGF-1 receptor RNA. The growth of all three cell lines is inhibited by an antisense oligodeoxynucleotide to IGF-1 receptor RNA or by peptide analogues of IGF-1 that compete with IGF-1 binding to its receptor. Our results indicate that these three cell lines grow by an autocrine loop in which the overproduced IGF-1 activates its receptor. Interference with the activation of the receptor leads to cessation of growth.

235 citations


Journal ArticleDOI
TL;DR: It is suggested that the differentiating action of NGF in PC12 cells might be due, at least in part, to the conjunction of its sustained and robust stimulation of ERK1 and pp90rsk, and of its induction ofERK1 nuclear translocation.

228 citations


Journal ArticleDOI
TL;DR: The results suggest that IGF‐I may play an important role in stimulating the growth and progression of prostate cancer.
Abstract: The role of insulin-like growth factor I (IGF-I) in the growth and development of prostate cancer was studied using established human prostate cancer cell lines. Under steroid and growth factor-free culture conditions, IGF-I significantly stimulated the androgen-independent cell lines PC-3 and DU-145 to incorporate [3H]thymidine into DNA, while the androgen-dependent cell line, LNCaP, was not affected. However, in the presence of dihydrotestosterone (DHT), DNA synthesis of LNCaP cells was stimulated by IGF-I in a dose-dependent manner. None of the cell lines tested secreted an immunoreactive level of IGF-I into their conditioned medium. Characterization of receptors by ligand binding assays revealed that all prostate cancer cell lines tested express specific binding sites for IGF-I with similar dissociation constants (0.23-0.39 nM). Crosslinking studies supported the suggestion that 125I-IGF-I was bound to a receptor on these cells. The IGF-I receptor concentrations of androgen-independent cell lines were significantly higher than those of the androgen-dependent cell line. Androgen appeared to affect neither the expression of IGF-I receptors nor the secretion of IGF-I. The results suggest that IGF-I may play an important role in stimulating the growth and progression of prostate cancer.

216 citations


Journal Article
TL;DR: Human corneal epithelial, stromal fibroblasts, and endothelial cells produce messenger RNA coding for HGF and KGF, although low levels appear to be present in the epithelial cells.
Abstract: Purpose. The purpose of this study was to determine whether messenger RNA coding for hepatocyte growth factor (HGF), HGF receptor (MET), keratinocyte growth factor (KGF), KGH receptor, and fibroblast growth factor (FGF) receptor-2 were produced in primary cultures of human corneal epithelial, stromal fibroblast, and endothelial celss, as well as ex vivo corneal epithelium, endothelial cells transfected with the SV40 large T antigen, and control embryonic lung fibroblasts. The effects of exogenous HGF and KGF, compared to epidermal growth factor, on the proliferation of first passage corneal cells were also examined

Journal ArticleDOI
TL;DR: Effective growth factors may stimulate different, but partially overlapping, molecular pathways during developmental differentiation, and none of the factors stimulates dopaminergic cell differentiation comparable to the pronounced trophic action of nerve growth factor on peripheral sympathetic or basal forebrain cholinergic neurons.

Journal ArticleDOI
Napoleone Ferrara1
TL;DR: The VEGF protein has therapeutic potential as an inducer of neovascularization in conditions characterized by impaired tissue perfusion like obstructive atherosclerosis and may be used for the treatment of malignancies and, possibly, other angiogenic diseases.

Journal ArticleDOI
TL;DR: This study suggests that the aberrant expression of VEGF receptors is one of the phenotypic changes occurring in melanoma cells during malignant transformation.

Journal ArticleDOI
TL;DR: It is indicated that transforming growth factor alpha is a trophic factor for mesencephalic cells in culture and suggests that transforminggrowth factor alpha plays a physiological role in the development of these cells in vivo.

Journal Article
TL;DR: D-limonene induces the regression of advanced rat mammary adenocarcinomas and the terpene-induced regression of mammary tumors may result in part from the mitoinhibitory and differentiation properties of active transforming growth factor beta 1.
Abstract: The monoterpenes represent a potentially new class of breast cancer therapeutic agents. We have shown that d -limonene induces the regression of advanced rat mammary adenocarcinomas. These regressing tumors have an increased cellular concentration of both the mannose-6-phosphate/insulin-like growth factor II receptors and transforming growth factor β1. The terpene-induced regression of mammary tumors may result in part from the mitoinhibitory and differentiation properties of active transforming growth factor β1. Furthermore, the activation of transforming growth factor β1 in these tumors is likely to be facilitated by the increased concentration of the mannose-6-phosphate/insulin-like growth factor II receptors in the mammary tumor cells. Tumors not responding to terpene therapy lacked a rise in the mannose-6-phosphate/insulin-like growth factor II receptor level which may relate to the fact that this gene is hemizygous due to maternal imprinting.

Journal ArticleDOI
TL;DR: The induced expression of the heparan sulfate co-receptor (syndecan-1) may provide a mechanism to restrict FGF action and modulate cell-matrix interactions to maintain co-ordinated growth of cells during organ formation.

Journal ArticleDOI
TL;DR: Experiments with the drug suramin suggest that growth factors do not only transduce the UV-induced signal to nonirradiated cells but act on the producer cell thus establishing an obligatory growth factor loop for at least part of the UV response.

Journal ArticleDOI
Joy L. Ware1
TL;DR: The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone.
Abstract: Prostate adenocarcinoma, the most common tumor occuring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of these, especially EGF, bFGF, and TGF-beta, are also implicated in growth regulation in normal and benign hyperplastic prostates. Although evidence fromin vitro study of the small number of prostate cell lines available demonstrates that these growth regulatory pathways are exploited by some of these cells, directin vivo evidence is limited. The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone. The progression and metastasis of human prostate cancer results from the complex interactions ofmultiple growth factors, androgens, and cellular communication, which form a dynamic network. Continued progress in the study and treatment of this disease will require new conceptual frameworks as well as successful application of the techniques of molecular and cellular biology.


Journal ArticleDOI
TL;DR: Binding studies with glutathione S-transferase fusion proteins indicate that Grb2 binds two distinct subsets of proteins which are individually recognized by its SH2 and SH3 domains, adding further support to the concept that GrB2 is a modular adaptor protein.
Abstract: We report the isolation and molecular characterization of the mouse grb2 gene. The product of this gene, the Grb2 protein, is highly related to the Caenorhabditis elegans sem-5 gene product and the human GRB2 protein and displays the same SH3-SH2-SH3 structural motifs. In situ hybridization studies revealed that the mouse grb2 gene is widely expressed throughout embryonic development (E9.5 to P0). However, grb2 transcripts are not uniformly distributed, and in certain tissues (e.g., thymus) they appear to be regulated during development. Recent genetic and biochemical evidence has implicated the Grb2 protein in the signaling pathways that link cell surface tyrosine kinase receptors with Ras. We have investigated the association of the Grb2 protein with epidermal growth factor (EGF) and nerve growth factor (NGF) receptors in PC12 pheochromocytoma cells. EGF treatment of PC12 cells results in the rapid association of Grb2 with the activated EGF receptors, an interaction mediated by the Grb2 SH2 domain. However, Grb2 does not bind to NGF-activated Trk receptors. Mitogenic signaling of NGF in NIH 3T3 cells ectopically expressing Trk receptors also takes place without detectable association between Grb2 and Trk. These results suggest that whereas EGF and NGF can activate the Ras signaling pathway in PC12 cells, only the EGF receptor is likely to do so through a direct interaction with Grb2. Finally, binding studies with glutathione S-transferase fusion proteins indicate that Grb2 binds two distinct subsets of proteins which are individually recognized by its SH2 and SH3 domains. These observations add further support to the concept that Grb2 is a modular adaptor protein.

Journal ArticleDOI
TL;DR: This is the first demonstration of an exclusive function of TNF-R-75 in cells of epithelial origin and the search for a specific function was able to show that p75 is the specific receptor for T NF-mediated up-regulation of transforming growth factor alpha mRNA, whereas p55 is the signal transducer forTNF-induced up- regulation of epidermal growth factor receptor mRNA.

Journal Article
TL;DR: It is shown that several adult human primary fibroblast cultures from breast and prostate produce HGF/SF, and that MRC-5 HGF expression is inhibited by several known peptide growth factors, including transforming growth factor beta, epidermal growth factor, and transforming growth factors alpha.
Abstract: Hepatocyte growth factor/scatter factor (HGF/SF) is a stromally derived modulator of epithelial cell proliferation and morphology. To better assess the potential role of HGF/SF in tumor progression we sought to identify factors and biological conditions which regulate its expression. We show that several adult human primary fibroblast cultures from breast and prostate produce HGF/SF. HGF expression in the MRC-5 human fetal lung fibroblast cell line is stimulated by conditioned media harvested from human breast tumor cell lines (MCF-7, T47D, and MDA-MB-231). In contrast, both indirect and direct coculture of each of these tumor lines with MRC-5 fibroblasts down-regulates HGF/SF expression. Finally, we show that MRC-5 HGF expression is inhibited by several known peptide growth factors, including transforming growth factor β, epidermal growth factor, and transforming growth factor α.

Journal ArticleDOI
TL;DR: Results indicate that keratinocytes produce IL-7 in biologically relevant amounts, which, in turn, serve to promote the survival and growth of DETC, which is one mechanism to sustain the indefinite residence of gamma delta T cells in epithelial tissues of mice.

Journal Article
TL;DR: This review considers the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families and presents evidence that demonstrates both the potential and the importance of the FGF family in transformation and induction of metastasis.
Abstract: Polypeptide growth factors are a diverse group of biological regulators. Because they are fundamentally involved in the cellular processes that are important for transformation and progression to malignancy, alterations in growth factor control and in their signal pathways are often observed in tumor cells. In this review, we consider the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families. We explore the hypothesis that although abrogation of TGF-beta negative growth regulation is necessary for transformation, in the later stages of tumor progression, TGF-beta plays a direct role in the enhancement of invasion and metastasis as an autocrine stimulator of these processes. In addition, we present evidence that demonstrates both the potential and the importance of members of the FGF family in transformation and induction of metastasis. Several models of growth factor regulation of malignancy are presented in which we demonstrate (1) a link between TGF-beta 1 mitogenic stimulation of malignant cells and alterations in the expression of ribonucleotide reductase, a key rate-limiting step in the synthesis of DNA and in cell proliferation; (2) autocrine and/or intracrine FGF mitogenic stimulation of malignant cell proliferation and metastasis; and (3) autocrine TGF-beta regulation of malignant cell locomotion and invasion through elevated proteolytic activity and increased synthesis of hyaluronan and RHAMM, a novel hyaluronan cell surface receptor.

Journal Article
TL;DR: Findings indicate that IL-1α is an autocrine growth stimulator for gastric carcinoma cells and the interaction with epidermal growth factor/transforming growth factor α/receptor system should be involved in the growth modulation by IL- 1α.
Abstract: The expression and effect of interleukin 1α (IL-1α) were examined in human gastric carcinoma cell lines to determine if IL-1α acts as a growth stimulator for these cells Six of 8 gastric carcinoma cell lines expressed IL-1α mRNA at various levels Among them, TMK-1 and MKN-7 cells secreted IL-1α into the culture fluid, in an especially large amount by MNK-7 cells Scatchard plot analysis of IL-1α binding revealed that TMK-1 cells had only one type of high-affinity receptors, whereas MKN-7 cells had high- and low-affinity receptors Cell growth and DNA synthesis of TMK-1 and MKN-7 cells were stimulated by IL-1α, and those of MKN-7 were inhibited by addition of anti-IL-1α antibody or IL-1 receptor antagonist The expression of IL-1α mRNA by these cell lines was induced by either IL-1α, epidermal growth factor, or transforming growth factor α On the other hand, IL-1α increased the mRNA expression for transforming growth factor α and epidermal growth factor receptor These findings indicate that IL-1α is an autocrine growth stimulator for gastric carcinoma cells and the interaction with epidermal growth factor/transforming growth factor α/receptor system should be involved in the growth modulation by IL-1α


Journal ArticleDOI
15 Feb 1993-Cancer
TL;DR: A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes.
Abstract: BACKGROUND: As in the case of other epithelial neoplasms, most ovarian cancers arise from single clones of cells that have undergone multiple genetic alterations. A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes. METHODS: Recent articles and abstracts have been reviewed. RESULTS: The malignant ovarian epithelial phenotype has been associated with (1) autocrine growth stimulation by transforming growth factor-alpha, (2) loss of autocrine growth inhibition by transforming growth factor-beta, (3) mutation or amplification of ras in 2-12% of cases, (4) amplification of myc in 23% of specimens, (5) expression of fms in 56% of cases with potential autocrine stimulation by macrophage colony stimulating factor, (6) paracrine stimulation by macrophage products including interleukin-1, interleukin-6 and tumor necrosis factor, (7) overexpression of c-erbB-2 (HER-2/neu) in 30% of cases, and (8) mutation with consequent overexpression of p53 in 50% of advanced ovarian cancers. A poor clinical prognosis is associated with expression or overexpression of the epidermal growth factor receptor, fms, and HER-2/neu. Antibodies against the extracellular domain of the HER-2/neu gene product p185 inhibit the growth of tumor cells that overexpress HER-2/neu and are associated with marked decreases in diacylglycerol levels. The intracellular kinase domain is required for growth inhibition. Antibodies that inhibit growth stimulate phosphorylation of intracellular substrates. Ricin A chain monoclonal antibody conjugates that react with p185 also inhibit the growth of tumor cells that overexpress p185. The intracellular kinase region is not required for immunotoxin-mediated killing. Coexpression of HER-2/neu and the epidermal growth factor receptor has been observed in 65% of epithelial ovarian cancers and in a limited number of normal tissue from a fraction of donors. CONCLUSIONS: Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.

Journal ArticleDOI
TL;DR: This view is supported by the recent finding that human melanoma cells that have been stably transfected with a PDGF B-chain cDNA, elicit a stroma response when transplanted to nude mice.
Abstract: Platelet-derived growth factor (PDGF) is a potent mitogen for a variety of cell types. PDGF is made up as dimers of A and B polypeptide chains which are combined to generate the three isoforms of PDGF (AA, AB, BB). These bind with different specificities and affinities to two types of cell surface receptors (the a-receptor and the /)-receptor), both being members of the protein tyrosine kinase family of growth factor receptors. A number of human tumor cell lines, particularly those established from glioma and sarcoma, have been shown to produce PDGF and express the cognate receptor type. In these instances, tumor cell growth may be enhanced by an autocrine receptor activation. In other tumor cell types, where PDGF is produced in the absence of receptor expression, the growth factor may act in a paracrine fashion. This view is supported by our recent finding that human melanoma cells that have been stably transfected with a PDGF B-chain cDNA, elicit a stroma response when transplanted to nude mice.

Journal Article
S Mii1, J A Ware1, K C Kent1
01 Jan 1993-Surgery
TL;DR: TGF-beta inhibits both migration and proliferation of human SMC and the signal transduction mechanisms through which TGF- beta exerts this effect are not mediated through protein kinase C, mitogen-activated protein kinases, or tyrosine kinases.