Showing papers on "Growth factor receptor inhibitor published in 2001"
TL;DR: Therapeutic approaches should aim to inhibit the TGF-β-induced invasive phenotype, but also to retain its growth-inhibitory and apoptosis-inducing effects.
710 citations
TL;DR: The role and regulation of IL-8 expression in the growth and metastasis of human cancer with a focus on human pancreatic adenocarcinoma will be discussed.
664 citations
Journal Article•
TL;DR: It is demonstrated that the antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local growth and facilitate angiogenesis, and that this effect can be potentiated by the combined treatment with certain cytotoxic drugs, such as paclitaxel.
Abstract: The transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha-EGFR) autocrine pathway, which is involved in the development and the progression of human epithelial cancers, controls, in part, the production of angiogenic factors. These angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are secreted by cancer cells to stimulate normal endothelial cell growth through paracrine mechanisms. ZD1839 (Iressa) is a p.o.-active, selective EGFR-tyrosine kinase inhibitor (TKI) in clinical trials in cancer patients. In this study, we evaluated the antiangiogenic and antitumor activity of ZD1839 in human colon (GEO, SW480, and CaCo2), breast (ZR-75-1 and MCF-7 ADR), ovarian (OVCAR-3), and gastric (KATO III and N87) cancer cells that coexpress TGF-alpha and EGFR. ZD1839 treatment determined a dose- and time-dependent growth inhibition accompanied by the decrease of VEGF, bFGF and TGF-alpha production in vitro. Treatment of immunodeficient mice bearing well-established, palpable GEO xenografts with ZD1839 determined a cytostatic dose-dependent tumor growth inhibition. Immunohistochemical analysis of GEO tumor xenografts after ZD1839 treatment revealed a significant dose-dependent reduction of TGF-alpha, bFGF, and VEGF expression in cancer cells and of neoangiogenesis, as determined by microvessel count. Furthermore, the antitumor activity of ZD1839 was potentiated in combination with the cytotoxic drug paclitaxel in GEO tumor xenografts. Tumor regression was observed in all mice after treatment with ZD1839 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of TGF-alpha, VEGF, and bFGF expression with a few or no microvessels. Furthermore, 6 of 16 mice bearing well-established, palpable GEO xenografts had no histological evidence of GEO tumors at the end of treatment with ZD1839 plus paclitaxel. These results demonstrate that the antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local growth and facilitate angiogenesis, and that this effect can be potentiated by the combined treatment with certain cytotoxic drugs, such as paclitaxel.
647 citations
TL;DR: ZD 1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours and the use of pharmacokinetic data in the development of ZD1839 is discussed.
532 citations
Journal Article•
TL;DR: Interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy is suggested.
Abstract: Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.
468 citations
TL;DR: This review focuses on the signal transduction properties of VEGF receptor-1 and VEGf receptor-2, and shows that most, if not all, of the factors and receptors in this family serve critical functions during vascular development or in adult physiological and pathological angiogenesis.
Abstract: Vascular endothelial growth factor (VEGF)/vascular permeability factor is the prototype for a growing family of dimeric growth factors, which exert their effects on vascular and lymphatic endothelial cells, as well as on a wide range of other cell types. Gene targeting shows that most, if not all, of the factors and receptors in this family serve critical functions during vascular development or in adult physiological and pathological angiogenesis. Growing tumours produce VEGF, and many different strategies for inhibiting tumour growth by inhibiting VEGF production are being tested in clinical trials at present. This review focuses on the signal transduction properties of VEGF receptor-1 and VEGF receptor-2.
395 citations
TL;DR: The temporal and spatial coordination of events are shown to modulate the environment in which other growth factors initiate cell cycle events, which provides another level of complexity in VSMC growth mechanisms.
Abstract: Vascular smooth muscle cells (VSMC) exhibit several growth responses to agonists that regulate their function including proliferation (hyperplasia with an increase in cell number), hypertrophy (an increase in cell size without change in DNA content), endoreduplication (an increase in DNA content and usually size), and apoptosis. Both autocrine growth mechanisms (in which the individual cell synthesizes and/or secretes a substance that stimulates that same cell type to undergo a growth response) and paracrine growth mechanisms (in which the individual cells responding to the growth factor synthesize and/or secrete a substance that stimulates neighboring cells of another cell type) are important in VSMC growth. In this review I discuss the autocrine and paracrine growth factors important for VSMC growth in culture and in vessels. Four mechanisms by which individual agonists signal are described: direct effects of agonists on their receptors, transactivation of tyrosine kinase-coupled receptors, generation of reactive oxygen species, and induction/secretion of other growth and survival factors. Additional growth effects mediated by changes in cell matrix are discussed. The temporal and spatial coordination of these events are shown to modulate the environment in which other growth factors initiate cell cycle events. Finally, the heterogeneous nature of VSMC developmental origin provides another level of complexity in VSMC growth mechanisms.
389 citations
TL;DR: Together, these data provide a signaling link between growth factor receptors and MAPK activation and a mechanistic explanation of the differential MAPK kinetics exhibited by these growth factors.
388 citations
TL;DR: It is proposed that non-hepatic tissue-derived IGF-I may be sufficient for growth and development and the original somatomedin hypothesis has undergone further modifications.
Abstract: ▪ Abstract The traditionally accepted theory has been that most of the biological effects of growth hormone (GH) are mediated by circulating (endocrine) insulin-like growth factor-I (IGF-I). This dogma was modified when it was discovered that most tissues express IGF-I that can act via an autocrine/paracrine fashion. In addition, both GH and IGF-I had independent effects on various target tissues. Using tissue-specific gene deletion of IGF-I in the liver, it has been shown that circulating IGF-I is predominantly liver-derived but is not essential for normal postnatal growth. Therefore, it is proposed that non-hepatic tissue-derived IGF-I may be sufficient for growth and development. Thus the original somatomedin hypothesis has undergone further modifications.
343 citations
TL;DR: Results from phase I and II trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancertreated with C 225 plus CPT-11, and in advanced pancreatic cancer treatedwith C225plus gemcitabine.
Abstract: Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.
339 citations
TL;DR: Analysis of the signaling pathways downstream of integrins, cadherins and growth-factor receptors are providing an insight into the molecular basis of known anti-angiogenic strategies, as well as into the design of novel therapies.
TL;DR: An antiestrogen-resistant MCF7 breast cancer cell subline (FASMCF) is established by continuous culture of the estrogen-responsive parental line in steroid-depleted, ICI 182,780 (Faslodex; 10(-7) M)-supplemented medium and cells show increased dependence upon epidermal growth factor receptor (EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling.
Abstract: This paper describes the establishment of an antiestrogen-resistant MCF7 breast cancer cell subline (FASMCF) by continuous culture of the estrogen-responsive parental line in steroid-depleted, ICI 182,780 (Faslodex; 10-7 M)-supplemented medium. After a 3-month period of growth suppression, cells began to proliferate in ICI 182,780 at rates similar to those of untreated wild-type cells. Immunocytochemistry showed these cells to have reduced estrogen receptor and an absence of progesterone receptor proteins. RT-PCR and transient transfection studies with estrogen response element-reporter constructs confirmed that ICI 182,780-suppressed estrogen response element-mediated signaling. FASMCF cells show increased dependence upon epidermal growth factor receptor (EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling. Thus, EgfR protein and messenger RNA, growth responses to transforming growth factor-, and extracellular signal-regulated kinase 1/2 MAPK activation levels are all increased. Unlike wild-type cells, FASMCF cells are highly sensitive to growth inhibition by an EgfR-specific tyrosine-kinase inhibitor (TKI), ZD1839 (Iressa), and an inhibitor of the activation of MEK1 (MAPKK), PD098059.
Short-term (3 weeks) withdrawal of cells from antiestrogen had no effect on growth or phenotype, whereas longer withdrawal (>10 weeks) appeared to partially reverse the cellular phenotype with increasing estrogen receptor and decreasing EgfR levels.
In subsequent studies FASMCF cells were maintained in TKI, where their growth was again suppressed and secondary TKI resistance failed to develop within the 3-month period in which initial ICI 182,780 resistance arose. Furthermore, wild-type cells similarly maintained in combination ICI 182,780 and TKI treatment conditions remained growth arrested (>6 months), with notable cell loss through both reduced rates of cellular proliferation and increased cell death.
TL;DR: It is shown that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group, which results in compounds with enhanced biological properties.
Abstract: A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.
TL;DR: It is demonstrated that MUC1 associates constitutively with the epidermal growth factor receptor (EGF-R) in human ZR-75-1 breast carcinoma cells and a novel role for EGF-R in regulating interactions of M UC1 with c-Src and β-catenin is supported.
TL;DR: IMC-C225, a novel monoclonal antibody that targets the EGFR, may prove to become a valuable contributor in the treatment of cancer.
Abstract: Treatment of solid tumors despite improved techniques in detection, surgery, radiation therapy, and chemotherapy remains difficult. Therefore, strategies to improve efficacy in accord with safety are needed. Many epithelial cancers have been found to overexpress the receptor to epidermal growth fact
TL;DR: A new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair is described.
Abstract: Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal–regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-“tethered” ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of “insoluble” growth factor ligands and a novel mode of activation for growth factor receptors.
TL;DR: It is suggested that DC101 inhibits angiogenesis, endothelial cell survival, and VEGF-mediated ascites formation in a murine model of colon cancer carcinomatosis, and combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon peritoneal carcinom atosis.
Abstract: Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) regulate colon cancer growth and metastasis. Previous studies utilizing antibodies against the VEGF receptor (DC101) or EGF receptor (C225) have demonstrated independently that these agents can inhibit tumour growth and induce apoptosis in colon cancer in in vivo and in vitro systems. We hypothesized that simultaneous blockade of the VEGF and EGF receptors would enhance the therapy of colon cancer in a mouse model of peritoneal carcinomatosis. Nude mice were given intraperitoneal injection of KM12L4 human colon cancer cells to generate peritoneal metastases. Mice were then randomized into one of four treatment groups: control, anti-VEGFR (DC101), anti-EGFR (C225), or DC101 and C225. Relative to the control group, treatment with DC101 or with DC101+C225 decreased tumour vascularity, growth, proliferation, formation of ascites and increased apoptosis of both tumour cells and endothelial cells. Although C225 therapy did not change any of the above parameters, C225 combined with DC101 led to a significant decrease in tumour vascularity and increases in tumour cell and endothelial cell apoptosis (vs the DC101 group). These findings suggest that DC101 inhibits angiogenesis, endothelial cell survival, and VEGF-mediated ascites formation in a murine model of colon cancer carcinomatosis. The addition of C225 to DC101 appears to lead to a further decrease in angiogenesis and ascites formation. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon peritoneal carcinomatosis.
TL;DR: By virtue of its growth regulatory and immunomodulatory properties, TGF‐β promises to become a novel target for the experimental therapy of human malignant glioma.
Abstract: Characteristics of human malignant glioma are excessive proliferation, infiltrative growth, angiogenesis and suppression of anti-tumor immune surveillance. Transforming growth factor-beta (TGF-β), a versatile cytokine, is intimately involved in the regulation of these processes. Here, we discuss the interactions of TGF-β with growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF), metalloproteinases (MMP-2, MMP-9) and their inhibitor, plasmin activator inhibitor-1 (PAI-1), and immune cells, like natural killer cells, T-cells and microglia. The differential effects of TGF-β in glioma biology are outlined with emphasis on the induction of a survival advantage for glioma cells by enforced cell growth, migration, invasion, angiogenesis and immune paralysis. By virtue of its growth regulatory and immunomodulatory properties, TGF-β promises to become a novel target for the experimental therapy of human malignant glioma. Microsc. Res. Tech. 52:401–410, 2001. © 2001 Wiley-Liss, Inc.
TL;DR: The nature, prevalence, and significance of TGF‐β signaling pathway alterations in various forms of human cancer as well as potential preventive and therapeutic interventions are discussed in this review.
Abstract: Transforming growth factor beta (TGF-beta) is an effective and ubiquitous mediator of cell growth. The significance of this cytokine in cancer susceptibility, cancer development and progression has become apparent over the past few years. TGF-beta plays various roles in the process of malignant progression. It is a potent inhibitor of normal stromal, hematopoietic, and epithelial cell growth. However, at some point during cancer development the majority of transformed cells become either partly or completely resistant to TGF-beta growth inhibition. There is growing evidence that in the later stages of cancer development TGF-beta is actively secreted by tumor cells and not merely acts as a bystander but rather contributes to cell growth, invasion, and metastasis and decreases host-tumor immune responses. Subtle alteration of TGF-beta signaling may also contribute to the development of cancer. These various effects are tissue and tumor dependent. Identifying and understanding TGF-beta signaling pathway abnormalities in various malignancies is a promising avenue of study that may yield new modalities to both prevent and treat cancer. The nature, prevalence, and significance of TGF-beta signaling pathway alterations in various forms of human cancer as well as potential preventive and therapeutic interventions are discussed in this review.
TL;DR: In examining the basal expression of estrogen-induced genes in the stable transfectants or in transient cotransfection assays with an estrogen-response element- reporter construct and Δraf or constitutively active MAPK kinase (ΔMEK), no ligand- independent activation of ERα was observed.
Abstract: ERα-negative breast tumors tend to overexpress growth factor receptors such as epidermal growth factor receptor or c-erbB-2 Raf-1 is a key intermediate in the signal transduction pathways of these receptors High levels of constitutive Raf kinase (Δraf) activity imparts ERα- positive MCF-7 breast cancer cells with the ability to grow in the absence of estrogen Δraf transfectants maintained in estrogen-depleted media showed greatly diminished responses to 17β-estradiol or the pure antiestrogen ICI 182,780 Western blotting, ligand binding, and immunohistochemistry assays revealed a loss of ERα protein expression, and ribonuclease protection assays indicated that this correlated with loss of ERα message In examining the basal expression of estrogen-induced genes in the stable transfectants or in transient cotransfection assays with an estrogen-response element- reporter construct and Δraf or constitutively active MAPK kinase (ΔMEK), no ligand- independent activation of ERα was observed Transient express
TL;DR: Utilizing the conditional gene-deletion approach, it is demonstrated that mice lacking the liver IGF-I gene have an approximately 80% reduction in circulating total IGF- I levels, suggesting that liver IGF -I is not essential for this function.
Abstract: The insulin-like growth factors (IGF-I and IGF-II) and the IGF-I receptor are critically important for normal growth and development of the organism. Gene-deletion of these elements has demonstrated that IGF-I is important for both prenatal and postnatal development, whereas IGF-II is important during prenatal stages only. The IGF-I receptor gene-deleted mouse dies at birth apparently as a result of poor muscular development. Utilizing the conditional gene-deletion approach, we have demonstrated that mice lacking the liver IGF-I gene have an approximately 80% reduction in circulating total IGF-I levels. Despite this marked reduction, postnatal growth and development was normal, suggesting that liver IGF-I is not essential for this function. Local tissue IGF-I production was unaffected and may compensate for the lack of the liver IGF-I. Further studies are ongoing to establish the role of the endocrine vs. the autocrine/paracrine IGF-I.
TL;DR: D disruption of the 5‐LO signaling pathway mediates growth arrest and apoptosis in breast cancer cells, and additional experiments suggest that this involves the interplay of several factors, including the loss of growth stimulation by 5‐ LO products, the induction of PPARγ, and the potential activation of PParγ by interactions with shunted endoperoxides.
Abstract: SPECIFIC AIMSIn recent studies we have described the function of various arachidonic acid (AA) metabolites in the growth regulation of aerodigestive cancers demonstrating overexpression of IGF-R and its ligand as conserved features of lung cancer and breast cancer. In lung cancer, IGF-1-dependent growth stimulation and a survival effect can be neutralized by blocking five-lipoxygenase (5-LO). We now address the hypothesis that products of 5-LO activity participate in the growth stimulation of breast cancer cells and reciprocally how other specific AA metabolites arising as a consequence of blockage of 5-LO activity may be relevant in the inhibition of breast cancer growth.PRINCIPAL FINDINGS1. Production of the 5-LO metabolite 5-HETE occurs in vitro and mediates growth stimulationInsulin-like growth factor 1 (IGF-1) stimulation of breast cancer cells induces the activity of the 5-LO enzyme as demonstrated by a specific RIA for 5-HETE. Four breast cancer cell lines were exposed to IGF-1 or transferrin, resu...
TL;DR: This review is designed not to discuss all the identified factors in detail but to highlight some of the basic principles of growth factor action in the intestine, mainly on classical growth factors rather than interleukins and interferons.
Abstract: A continuously increasing number of regulatory peptides has been demonstrated to be expressed in the intestine and to modulate several functional properties of various intestinal cell populations, including the intestinal epithelium and lamina propria cell populations. These regulatory peptides include members of the epidermal growth factor (EGF) family, the transforming growth factor beta (TGF-beta) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the trefoil factor (TFF) family, the colony-stimulating factor (CSF) family, and a few other seemingly unrelated regulatory peptides, such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and various interleukins, interferons and tumour necrosis factor-related proteins. In addition to the well-known effects on cell proliferation, these regulatory peptide factors regulate several other functional properties of epithelial and other cell populations, such as differentiation, migration, and extracellular matrix deposition and degradation. This review is designed not to discuss all the identified factors in detail but to highlight some of the basic principles of growth factor action in the intestine. It focuses mainly on classical growth factors rather than interleukins and interferons.
TL;DR: It is found that VEGF, FGF-2, EGF and their receptors were all expressed, especially in and/or around blood vessels, thus supporting the hypothesis that these peptides contribute to the regulation of angiogenesis and blood vessel function in the human endometrium.
Abstract: Angiogenesis is an important but poorly understood process of the cycling endometrium. Endometrial angiogenesis is believed to be regulated by angiogenic growth factors under the influence of ovarian steroids. Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2, fibroblast growth factor 2 (FGF-2) and its receptors FGFR-1 and FGFR-2, as well as epidermal growth factor (EGF) and its receptor EGFR are believed to be important in the control of angiogenesis in the human endometrium. Their expression was examined by immunohistochemistry in endometrial biopsies obtained from 16 healthy women with proven fertility. Western blot analysis showed that the primary antibodies used were specific for their epitopes. We found that VEGF, FGF-2, EGF and their receptors were all expressed, especially in and/or around blood vessels, thus supporting the hypothesis that these peptides contribute to the regulation of angiogenesis and blood vessel function in the human endometrium. The receptors VEGFR-1, VEGFR-2, FGFR-2 and EGFR were co-expressed and exhibited their strongest expression during the beginning of the secretory phase, coinciding with the developing endometrial oedema and formation of a complex subepithelial capillary plexus. No correlation was seen between receptor expression and stromal blood vessel density.
Journal Article•
TL;DR: Targeting growth factor pathways, in addition to ER, is a developing strategy that hypothetically may represent optimal therapy by preventing the development of resistance to endocrine therapy.
Abstract: Breast cancer development and progression are directly related to the effects of the female hormone estrogen. The nuclear receptor for estrogen (ER) functions as a transcription factor controlling estrogen-regulated genes. Receptor conformation on ligand binding, its interaction with various coregulators, and response elements in the promoter region of target genes all contribute to the net estrogenic effects in a cell. ER is an important diagnostic and therapeutic target in breast cancer. Various polypeptide growth factors and their membrane receptors also contribute to breast cancer development and progression. Pathways mediating cell survival, cell proliferation, and response to stress not only generate signals through various protein kinase pathways to enhance cell survival and proliferation, but these pathways also interact with ERs. Kinases in the growth factor cascade can phosphorylate and activate ER, and ER in turn activates and augments signaling through the growth factor pathways. Signaling through the growth factor pathways may contribute to hormonal resistance states by ligand-independent activation of ER. Targeting growth factor pathways, in addition to ER, is a developing strategy that hypothetically may represent optimal therapy by preventing the development of resistance to endocrine therapy.
Journal Article•
TL;DR: Results indicate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of F GF-producing cerebral malignancies and may disrupt both angiogenesis-dependent and -independent signals required for glioma growth and invasion.
Abstract: We undertook a series of systematic studies to address the role of fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) activity in tumor growth and angiogenesis. We expressed dominant-negative FGFR2 (FGFR2-DN) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracycline-regulated expression systems. Anchorage-dependent or independent growth was inhibited in FGFR-DN-expressing cells. Tumor development after xenografting FGFR-DN-expressing cells in immunodeficient mice or after transplantation in rat brain was strongly inhibited. Quantification of microvessels demonstrated a significant decrease in vessel density in tumors derived from FGFR-DN-expressing cells. Furthermore, in a rabbit corneal assay, the angiogenic response after implantation of FGFR-DN-expressing cells was decreased. In tumors expressing FGFR-DN, vascular endothelial growth factor expression was strongly inhibited as compared with control tumor. These results indicate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of FGF-producing cerebral malignancies and may disrupt both angiogenesis-dependent and -independent signals required for glioma growth and invasion.
TL;DR: The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.
Abstract: There is an increasing body of evidence demonstrating that growth factor networks are highly interactive with oestrogen receptor (ER) signalling in the control of breast cancer growth. As such, tumour responses to anti- hormones are likely to be a composite of the ER and growth factor inhibitory activity of these agents. The current article examines the modulation of growth factor networks during endocrine response, and presents in vitro and clinical evidence that epidermal growth factor receptor signalling, maintained in either an ER-dependent or -independent manner, is critical to anti- hormonal-resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.
TL;DR: These findings implicate sex steroids as an important stimulus for vascular endothelial growth factor regulation in hormone sensitive tumors and demonstrate the reversal of neovascularization after hormone withdrawal as an early event in the tumor response to therapy.
TL;DR: A tethered receptor complex provides a platform on which receptor tyrosine kinase and G-protein-coupled receptor signals can be integrated to produce more efficient stimulation of the p42/p44 mitogen-activated protein kinase pathway.