Showing papers on "Growth factor receptor inhibitor published in 1995"
2,746 citations
TL;DR: The biological actions of the IGFs are modulated by a family of at least six IGF-binding proteins (IGFBPs) that are found in the circulation and in extracellular compartments and are produced by most tissues.
Abstract: I. Introduction THE insulin-like growth factors (IGFs) and their receptors and binding proteins constitute a family of cellular modulators that play essential roles in the regulation of growth and development. The IGF ligands include three structurally related peptides: insulin, IGF-I, and IGF-II. Unlike insulin, IGF-I and IGF-II are expressed ubiquitously, albeit in a highly regulated manner (see reviews in Refs. 1-5). The biological functions of the IGFs are mediated by a family of transmembrane receptors, which includes the insulin, IGF-I, and IGF-II/mannose-6-phosphate (M-6-P) receptors. While the IGF-I receptor is the primary mediator of IGF action, the insulin and IGF-II/M-6-P receptors may also mediate some of these functions (Fig. 1) (6, 7). The biological actions of the IGFs are modulated by a family of at least six IGF-binding proteins (IGFBPs) that are found in the circulation and in extracellular compartments and are produced by most tissues. The IGFBPs are capable of inhibiting or enhancing I...
1,406 citations
TL;DR: It is found that EGF-R-/- mice survive for up to 8 days after birth and suffer from impaired epithelial development in several organs, including skin, lung and gastrointestinal tract.
Abstract: Since the discovery that epidermal growth factor (EGF) can accelerate opening of the eyelids, the EGF receptor (EGF-R) has been extensively studied and is now considered to be a prototype tyrosine kinase receptor. Binding of EGF or of transforming growth factor-alpha (TGF-alpha) or other related factors activates the receptor and induces cell proliferation and differentiation. Although it is not found on haematopoietic cells, the EGF-R is widely expressed in mammals and has been implicated in various stages of embryonic development. Here we investigate the developmental and physiological roles of this receptor and its ligands by inactivating the gene encoding EGF-R. We find that EGF-R-/- mice survive for up to 8 days after birth and suffer from impaired epithelial development in several organs, including skin, lung and gastrointestinal tract.
1,036 citations
Patent•
23 May 1995TL;DR: In this article, a method of treating tumor cells with antibodies which inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis factor, is also disclosed.
Abstract: A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or growth factor by treatment of the cells with antibodies which inhibit the growth factor receptor function, is disclosed. A method of treating tumor cells with antibodies which inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are rendered more susceptible to cytotoxic factors.
678 citations
TL;DR: Important aspects of IGFs in normal cell growth and their role in certain malignancies are highlighted and IGFs may enhance in vivo tumor cell formation, growth, and even metastasis.
Abstract: The insulin-like growth factor (IGF) family of peptides, binding proteins, and receptors are important for normal human growth and development and are involved in the specialized functions of most physiologic systems. Most members of the IGF system are expressed by different cancer cells and may play an important role in the propagation of these malignancies. New therapies aimed at modulating various components of the IGF system could affect the progression and metastasis of cancer.
656 citations
Journal Article•
TL;DR: Findings indicate that the IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions.
Abstract: The insulin-like growth factor I receptor (IGF-IR) belongs to the family of transmembrane tyrosine kinase receptors, like the receptors for platelet-derived growth factor, the epidermal growth factor, insulin, and others. Genetic evidence has shown that the IGF-IR is required for optimal growth in vitro and in vivo. Even more important, however, have been recent findings from several laboratories clearly showing that the IGF-IR is an absolute requirement for the establishment and maintenance of the transformed phenotype, both in vivo and in vitro and in several cell types. These findings indicate that the IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions.
606 citations
TL;DR: The results suggest an association between activation of p44mapk and both TGF-β- mediated growth inhibition and EIT-mediated growth stimulation, which suggests that the specificity for the cellular effects of growth factors may not occur at the level of MAPK activation per se, but rather at downstream events that include phosphorylation of distinct transcriptional complexes and activation of a select assortment of genes.
321 citations
TL;DR: A potent protein-tyrosine kinase inhibitor that shows selectivity for the PDGF receptor in vitro and in the cell, CGP 53716 may have therapeutic potential for the treatment of diseases involving abnormal cellular proliferation induced byPDGF receptor activation.
Abstract: The platelet-derived growth factor (PDGF) receptor is a member of the transmembrane growth factor receptor protein family with intrinsic protein-tyrosine kinase activity. We describe a potent protein-tyrosine kinase inhibitor (CGP 53716) that shows selectivity for the PDGF receptor in vitro and in the cell. The compound shows selectivity for inhibition of PDGF-mediated events such as PDGF receptor autophosphorylation, cellular tyrosine phosphorylation, and c-fos mRNA induction in response to PDGF stimulation of intact cells. In contrast, ligand-induced autophosphorylation of the epidermal growth factor (EGF) receptor, insulin receptor, and the insulin-like growth factor I receptor, as well as c-fos mRNA expression induced by EGF, fibroblast growth factor, and phorbol ester, was insensitive to inhibition by CGP 53716. In antiproliferative assays, the compound was approximately 30-fold more potent in inhibiting PDGF-mediated growth of v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/Mk cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line. When tested in vivo using highly tumorigenic v-sis- and human c-sis-transformed BALB/c 3T3 cells, CGP 53716 showed antitumor activity at well-tolerated doses. In contrast, CGP 53716 did not show antitumor activity against xenografts of the A431 tumor, which overexpresses the EGF receptor. These findings suggest that CGP 53716 may have therapeutic potential for the treatment of diseases involving abnormal cellular proliferation induced by PDGF receptor activation.
294 citations
TL;DR: Comparisons with established characteristics of erythropoietin regulation indicate that a similar mechanism of oxygen sensing is operating on a variety of vascular growth factors, and they suggest that chelatable iron is closely involved in the mechanism.
Abstract: Recent work has indicated that oxygen-sensing mechanism(s) resembling those controlling erythropoietin production operate in many non-erythropoietin-producing cells. To pursue the implication that such a system might control other genes, we studied oxygen-regulated expression of mRNAs for vascular endothelial growth factor, platelet-derived growth factor (PDGF) A and B chains, placental growth factor (PLGF), and transforming growth factor in four different cell lines and compared the characteristics with those of erythropoietin regulation. Oxygen-regulated expression was demonstrated for each gene in at least one cell type. However, the response to hypoxia (1% oxygen) varied markedly, ranging from a 13-fold increase (PDGF-B in Hep G2 cells) to a 2-fold decrease (PLGF in the trophoblastic line BeWo). For each gene/cell combination, both the magnitude and direction of the response to hypoxia were mimicked by exposure to cobaltous ions or two different iron-chelating agents, desferrioxamine and hydroxypyridinones. These similarities with established characteristics of erythropoietin regulation indicate that a similar mechanism of oxygen sensing is operating on a variety of vascular growth factors, and they suggest that chelatable iron is closely involved in the mechanism.
274 citations
TL;DR: New insights have begun to emerge only recently on the normal function of these growth factors in mice and humans, as a result of studies of natural and experimental mutations in the factors and their receptors.
257 citations
TL;DR: Using Hs578T cells, it is demonstrated that TGF-β stimulates IGF BP-3 gene expression and production prior to its inhibition of cell growth, and treatment with an IGFBP-3 antisense oligodeoxynucleotide selectively inhibits T GF-β-induced IGFBP -3 synthesis and cell growth inhibition.
TL;DR: It is demonstrated that the angiogenic factor vascular endothelial growth factor (VEGF) activates mitogen-activated protein kinase (MAPK) as has been previously shown for basic fibroblast growth factor.
Abstract: A number of factors both stimulating and inhibiting angiogenesis have been described. In the current work, we demonstrate that the angiogenic factor vascular endothelial growth factor (VEGF) activates mitogen-activated protein kinase (MAPK) as has been previously shown for basic fibroblast growth factor. The antiagiogenic factor 16-kDa N-terminal fragment of human prolactin inhibits activation of MAPK distal to autophosphorylation of the putative VEGF receptor, Flk-1, and phospholipase C-gamma. These data show that activation and inhibition of MAPK may play a central role in the control of angiogenesis.
TL;DR: Findings suggest that factors known to act on endothelial cells and stimulate neovascularization may simultaneously serve to recruit mast cells to these sites of angiogenesis, which is believed to facilitate new vessel formation through complex cell:cell interactions.
Journal Article•
TL;DR: It is shown that both the V EGF receptors, FLT-1 and flk/KDR, are expressed in endothelial cells that line tumor-embedded microvascular vessels, suggesting that VEGF but not PlGF, contributes to thyroid tumor development.
Abstract: Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells in vitro, promotes neoangiogenesis in vivo and increases the permeability of the vascular endothelium. VEGF overexpression occurs in several cultured tumor cell lines and in certain human malignancies. Placenta growth factor (PlGF) is a recently identified growth factor for endothelial cells (EC); PlGF strongly potentiates both the proliferative and the permeabilization effects exerted by VEGF on the vascular endothelium. To uncover the molecular mechanisms underlying neoangiogenesis in human thyroid tumors, we have analysed VEGF and PlGF expression in a panel of thyroid carcinoma cell lines with different tumorigenic potential as well as in human primary thyroid tumors. We show that a high tumorigenic potential is associated with an elevated VEGF expression in human thyroid tumor cell lines. Furthermore, VEGF overexpression occurs in 5/5 highly malignant anaplastic carcinomas. Papillary and follicular carcinomas express intermediate levels of VEGF mRNA. In contrast, PlGF expression is severely down regulated in the majority of thyroid tumor cell lines and in tumors. Furthermore, we show that both the VEGF receptors, FLT-1 and flk/KDR, are expressed in endothelial cells that line tumor-embedded microvascular vessels, suggesting that VEGF but not PlGF, contributes to thyroid tumor development.
TL;DR: This work presents and discusses how the available models most closely represent phases of in vivo angiogenesis and the development of vessel patency, generated by a coalescing of intracellular vacuoles.
Abstract: Angiogenesis in vivo is distinguished by four stages: subsequent to the transduction of signals to differentiate, stage 1 is defined as an altered proteolytic balance of the cell allowing it to digest through the surrounding matrix. These committed cells then proliferate (stage 2), and migrate (stage 3) to form aligned cords of cells. The final stage is the development of vessel patency (stage 4), generated by a coalescing of intracellular vacuoles. Subsequently, these structures anastamose and the initial flow of blood through the new vessel completes the process. We present and discuss how the available models most closely represent phases of in vivo angiogenesis. The enhancement of angiogenesis by hyaluronic acid fragments, transforming growth factor beta, tumor necrosis factor alpha, angiogenin, okadaic acid, fibroblast growth factor, interleukin 8, vascular endothelial growth factor, haptoglobin, and gangliosides, and the inhibition of the process by hyaluronic acid, estrogen metabolites, genestein, heparin, cyclosporin A, placental RNase inhibitor, steroids, collagen synthesis inhibitors, thrombospondin, fumagellin, and protamine are also discussed.
TL;DR: The possibility that VEGF is involved in the maintenance of permeable endothelium in islets of Langerhans, an observation that may have implications for islet cell physiology and diabetes is raised.
Abstract: Endocrine organs, such as the pancreatic islets of Langerhans, contain permeable, fenestrated endothelium that allows direct access of endocrine cells to the blood stream. Factors that control differentiation and maintenance of this highly specialized endothelium remain unknown. Vascular endothelial growth factor (VEGF) is a multifunctional growth factor that may be responsible for the homeostasis of endocrine endothelium; it is a selective mitogen for endothelial cells and is able to permeabilize endothelium. We have analyzed the expression of VEGF mRNA and protein in pancreatic islet cells of normal mice and during the different stages of tumor progression in a transgenic mouse model of beta-cell carcinogenesis. The 120-amino acid and the 164-amino acid isoforms of VEGF are expressed in normal islets of Langerhans and are moderately up-regulated during the stages of tumor development. Two high-affinity receptors for VEGF, flt-1 and flk-1, are expressed by endothelial cells both in normal islets and in the stages of tumorigenesis; these receptors are not up-regulated during this process. Our data raise the possibility that VEGF is involved in the maintenance of permeable endothelium in islets of Langerhans, an observation that may have implications for islet cell physiology and diabetes. While VEGF may also play an important role in the growth of new blood vessels during islet cell tumorigenesis, it cannot be the only factor required for the activation of tumor angiogenesis.
TL;DR: These results demonstrate that distinct signaling pathways can cross talk via the secretion of polypeptide growth factors and demonstrate a marked increase in sensitivity to the cytotoxic action of diphtheria toxin.
Abstract: We have used differential display PCR to search for mRNAs induced by delta Raf-1:ER, an estradiol-dependent form of Raf-1 kinase. Through this approach the gene encoding heparin-binding epidermal growth factor (HB-EGF) was identified as an immediate-early transcriptional target of oncogenic Raf kinases. Activation of delta Raf-1:ER and a conditional oncogenic form of B-Raf, delta B-RAF:ER, resulted in rapid and sustained induction of HB-EGF mRNA expression and secretion of mature HB-EGF from cells. Neutralizing anti-HB-EGF antisera prevented the delayed activation of the c-Jun amino-terminal kinases that is observed in cells transformed by delta Raf-1:ER. These results demonstrate that distinct signaling pathways can cross talk via the secretion of polypeptide growth factors. Furthermore, cells transformed by oncogenic Ras, which also induced HB-EGF expression, demonstrated a marked increase in sensitivity to the cytotoxic action of diphtheria toxin, for which the membrane anchored HB-EGF precursor acts as a cell-surface receptor.
TL;DR: It is shown that upon stimulation of human epidermal growth factor (EGF) receptor, p120 becomes strongly tyrosine-phosphorylated and associates with activated EGF receptor in vivo and is involved in an early step in the EGF signaling pathway that is conserved from nematodes to mammals.
TL;DR: Detailed analyses of the expression and function of members of the fibroblast growth factor (FGF) family and their recepotors have demonstrated that the FGF signalling pathways play essential roles in regulating cellular proliferation, differentiation and tissue patterning during vertebrate embryogenesis.
TL;DR: C cultured human retinal pigment epithelial (HRPE) cells express both KDR and flt‐1 receptors, bind VAS/VEGF on two high affinity sites (apparent Kd of 9 and 210 pM corresponding to 940 and 18,800 sites per cell) and proliferate or migrate upon recombinant VAS /VEGF addition.
Abstract: Vasculotropin (VAS), also called vascular endothelial growth factor (VEGF) or vascular permeability factor, is a secreted growth factor whose target cell specificity has been reported as restricted to vascular endothelium. Its effects are mediated by at least two distinct membrane-spanning tyrosine kinase receptors, KDR and flt-1, the expression of which also seems restricted to vascular endothelium. We describe here that cultured human retinal pigment epithelial (HRPE) cells express both KDR and flt-1 receptors, bind VAS/VEGF on two high affinity sites (apparent Kd of 9 and 210 pM corresponding to 940 and 18,800 sites per cell) and proliferate or migrate upon recombinant VAS/VEGF addition. HRPE cells also express the mRNA corresponding to the 121 and 165 amino acid forms of VAS/VEGF. HRPE cells release in their own culture medium and store in their extracellular matrix self-mitogenic and chemoattractant factors indistinguishable from 121 and 165 VAS/VEGF isoforms. The autocrine role of VAS/VEGF was confirmed by the inhibition of these bioactivities by neutralizing specific anti-VAS/VEGF antibodies. © 1995 Wiley-Liss, Inc.
TL;DR: The VEGF signalling system seems to be an appropriate target to inhibit tumour angiogenesis and metastases formation.
TL;DR: The results strongly suggest that the growth factors regulate in vivo muscle regeneration and would be accessible tools for future therapy of muscular disorders.
TL;DR: Data obtained with primary human breast cancer specimens indicate that growth factors synthesized by breast cancer cells have an important role in tumor development and progression but that these factors act in a true autocrine fashion only in a subset of tumors.
Abstract: Data obtained using long-established human breast cancer cell lines have suggested that autocrine growth factors secreted by the cells are important for their growth in vitro. Such data alone cannot definitively establish a role for autocrine growth factors in human breast cancer cell proliferation in vivo, but they create a paradigm that can be tested by analysis of data obtained with primary breast cancer cells and tissues. This review is aimed at examining experimental data obtained using fresh human breast cancer cells and tissues to determine whether the results obtained are consistent with predictions made by autocrine models of human breast cancer cell proliferation. Conceptually, for autocrine loops to be of primary importance in human breast cancer cell proliferation, breast cancer cells in vivo must 1) synthesize biologically active growth factors that are available to growth factor receptors, 2) synthesize the cognate growth factor receptors, 3) require the specific factors for proliferation, and 4) express the autocrine loop as a pathologic, rather than a physiologic, process. Since the proportion of tumors that express growth factors of a given family is consistently higher than the proportion of tumors that express the cognate receptors, it is likely that growth factor synthesis has an important, nonautocrine role in breast cancer progression as well. Data obtained with primary human breast cancer specimens indicate that growth factors synthesized by breast cancer cells have an important role in tumor development and progression but that these factors act in a true autocrine fashion only in a subset of tumors.
TL;DR: A role for the IGF-I receptor in the proliferation of human breast cancer cells is strongly supported and strategies using this type of technology may prove useful in cancer therapy.
Abstract: Insulin-like growth factors (IGFs) play an important role in cellular proliferation, and IGF action appears to be involved in tumorigenesis. To determine the role of the IGF-I receptor in breast cancer cell growth, we stably transfected MCF-7 breast cancer cells with a construct encoding an antisense RNA complementary to the region surrounding the translation initiation site of the IGF-I receptor messenger RNA (mRNA). Control cells were transfected with vector alone. Clones expressing the antisense RNA exhibited a 30% reduction in endogenous IGF-I receptor mRNA levels and a significant reduction in receptor protein levels, as measured by both ligand binding assays and Western blot analysis. Antisense-expressing clones expressed approximately 30,000 receptors/cell compared with approximately 48,000-58,000 receptors/cell in control (neo) cells (P < 0.05). Although endogenous RNA:RNA hybrids were demonstrable in antisense-expressing cells, our results suggest that the major effect of the antisense may be the reduction in mRNA levels and not via an inhibition of translation. The reduction in receptor expression reduced both IGF-I- and serum-stimulated cellular proliferation. The maximum cell number reached at 96 h in the presence of IGF-I (100 ng/ml) was significantly reduced in antisense-expressing clones (22,000-30,000) compared with that in control (neo) cells (39,000-42,000). Furthermore, IGF-I-induced c-fos gene expression was reduced by 30% in the clones expressing the antisense RNA. These results strongly support a role for the IGF-I receptor in the proliferation of human breast cancer cells and suggest that strategies using this type of technology may prove useful in cancer therapy.
TL;DR: The type III receptor protein may play a role in presenting TGFβ2 to the type II receptor and increase responsiveness to TGF β2 to a level comparable to that of TGFα1, stably transfected BAECs.
TL;DR: It is concluded that combination therapy of epidermal growth factor with intestinal trefoil factor could provide a more potent, safer approach to the treatment of human gastrointestinal ulceration.
Abstract: 1. The availability of recombinant epidermal growth factor provides a potentially exciting development for the treatment of gastrointestinal ulceration. However, because of its potent mitogenic activity, there is a need for strategies which reduce the dose required. Intestinal trefoil factor stimulates mucosal healing without increasing proliferation. Studies were undertaken to examine the biological effects of rat intestinal trefoil factor and/or human epidermal growth factor upon gastrointestinal epithelial cell functions pertinent to mucosal protection, using two wounding models. 2. The study of epithelial restitution in vitro demonstrated a marked synergistic effect on the rate of migration of the wound edge when intestinal trefoil factor was used in combination with epidermal growth factor. There was no increased cellular proliferation due to the addition of intestinal trefoil factor to the cells when given alone, or to the stimulatory effect of cells treated with epidermal growth factor. In the rat model of gastric ulceration, the presence of both epidermal growth factor and intestinal trefoil factor protected against the development of indomethacin-induced gastric lesions. 3. We conclude that combination therapy of epidermal growth factor with intestinal trefoil factor could provide a more potent, safer approach to the treatment of human gastrointestinal ulceration.
01 Jan 1995
TL;DR: The next frontier in cell biology and urology is to understand the complex language used by cells to communicate with each other in the microenvironment, and a working knowledge of peptide growth factors is essential today for the urologist, since new strategies to combat disease have and will stem from a greater understanding of the role of peptIDE growth factors in urology.
Abstract: The next frontier in cell biology and urology is to understand the complex language used by cells to communicate with each other in the microenvironment. The discovery of epidermal growth factor by Dr. Stanley Cohen at Vanderbilt University established the existence of peptide growth factors as the “words” of this language. Peptide growth factors are regulatory proteins that govern the response of the cell to injury and mediate the highly coordinated processes of cell growth, differentiation and death (apoptosis). Several oncogene proteins that contribute to neoplastic transformation are, in fact, single peptide growth factors or peptide growth factor receptors: c-erbB-2 (truncated epidermal growth factor receptor),’ c-sis (platelet derived growth factor-B)2 and int-2 (fibroblast growth factor-like).Z Consequently, aberrant expression of peptide growth factor or their receptors can directly contribute to uncontrolled growth resulting in hyperplasia and malignancy. A working knowledge of peptide growth factors is essential today for the urologist, since new strategies to combat disease have and will stem from a greater understanding of the role of peptide growth factors in urology. Numerous peptide growth factors have been identified since the discovery of epidermal growth factor. Peptide growth factors that share common structural properties and function have been grouped into superfamilies. Since the field of peptide growth factors is growing exponentially, this review will focus primarily on the members of the epidermal growth factor, fibroblast growth factor, insulin-like growth factor and transforming growth factor-p families (see Appendix). It should be emphasized that there are other peptide growth factors or cytokines that have not been addressed in this review, including the neurotropins, bombesin, platelet derived growth factor, and a host of hematological growth factors and cytokines that may be important in urological disease. Peptide growth factors may use either autocrine or paracrine pathways to signal cells in the microenvironment (fig. 1). A cell uses an autocrine pathway if the cell responds to the same peptide growth factor that it is simultaneously producing. A paracrine pathway is activated when 1 cell type elaborates a peptide growth factor but a different cell type responds to it. For example, keratinocyte growth factor is made by stromal cells but only epithelial cells have cell surface receptors and are stimulated by keratinocyte growth fa~tor.~ Finally, endocrine pathways may only be permissive by indirectly influencing the microenvironment by modulating the direct mediators, peptide growth factors. In the microenvironment, cell polarity is also important, since autocrine, paracrine and endocrine transmission of protein growth factor information in vivo can be across small, discrete and localized distances. Thus, peptide growth factors and hormones interact with cell receptors setting in motion a cascade FIG. 1. Signal transduction pathways in cellular microenvironment. Endocrine pathways may only have permissive effect but autocrine and paracrine signaling pathways directly mediate epithelial and stromal cell interactions.
TL;DR: FGF9 presents a unique case of ligand-receptor specificity and fulfills the criteria as a high affinity, heparin-dependent ligand for FGFR3.
Abstract: Fibroblast growth factors (FGF) are multifunctional, heparin binding polypeptides that share structural similarity, but differ in their target cell specificity and expression pattern Here we describe the cloning and expression of the mouse homologue of FGF9, and the use of a panel of soluble FGF receptors and genetically engineered cells to study its receptor binding specificity FGF9 is found to bind with high affinity (kd: 025 nM) to FGFR3, for which a specific ligand has not yet been identified FGF9 can also bind, albeit with a lower affinity, to FGFR2 but does not bind FGFR1 or FGFR4 There is no significant binding to either FGFR3 or FGFR2, expressed either as soluble receptors or in heparin sulfate deficient cells, in the absence of heparin Moreover, receptor binding of FGF9 requires heparin in a manner specific to the receptor type In conclusion FGF9 presents a unique case of ligand-receptor specificity and fulfills the criteria as a high affinity, heparin-dependent ligand for FGFR3
TL;DR: Some physiologic actions of peptide growth factors are dependent on ER, particularly growth factors, which are capable of eliciting ER-dependent activation of an ERE.
Abstract: Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. The mechanism by which the actions of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possibility that some of the actions of EGF may be mediated through the estrogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically induction of DNA synthesis and phosphatidylinositol turnover. In addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growth factors on activation of a consensus estrogen response element was assessed in Ishikawa human endometrial adenocarcinoma cells, which contain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ER. EGF and TGF alpha induced transcriptional activation of a consensus estrogen response element (ERE) in an ER-dependent manner in both cell types. In addition, insulinlike growth factor I (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Synergism between growth factors and estrogen was observed in both cell types, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted synergistically with 17 beta-estradiol. A protein kinase C inhibitor abolished the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TGF alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factors. In conclusion, some physiologic actions of peptide growth factors are dependent on ER. Indeed, growth factors are capable of eliciting ER-dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of peptide growth factors on the ER in BG-1 cells.
TL;DR: Wortmannin, a selective phosphatidylinositol 3-kinase inhibitor, completely blocks growth factor stimulated chemotaxis while having no effect on neutrophil migration stimulated with classical chemoattractants, suggesting that cell migration can be selectively controlled through the inhibition of distinct signal transduction events.