Showing papers on "Growth factor receptor inhibitor published in 2011"
TL;DR: The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets, and 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models.
Abstract: Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
163 citations
TL;DR: Molecular targets in non-small cell lung cancer that are in development or being clinically applied and their implications for developing novel anticancer therapies for this previously refractory malignancy are described.
156 citations
TL;DR: This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets.
Abstract: The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.
150 citations
TL;DR: A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti- FGFR activity and a new generation of specific pan-FGFR inhibitors.
136 citations
TL;DR: Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate is a novel nitric oxide (NO) chimera containing an nonsteroidal anti-inflammatory drug (NSAID) and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity.
Abstract: Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094) is a novel NO chimera containing an NSAID and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity. In this study, the effects and mechanism of action of GT-094 were investigated in RKO and SW480 colon cancer cells. GT-094 inhibited cell proliferation and induced apoptosis in both cell lines and this was accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and these responses were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated genes associated with cell growth [cyclin D1, hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR)], survival (bcl-2, survivin), and angiogenesis [vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2)]. Results of previous RNA interference studies in this laboratory has shown that these genes are regulated, in part, by specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 that are overexpressed in colon and other cancer cell lines and not surprisingly, GT-094 also decreased Sp1, Sp3 and Sp4 in colon cancer cells. GT-094-mediated repression of Sp and Sp-regulated gene products was due to downregulation of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to activation of an ROS-miR-27a:ZBTB10-Sp transcription factor pathway.
125 citations
TL;DR: Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance.
Abstract: Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.
124 citations
TL;DR: Light is shed on the mechanisms by which PSCs in the stroma influence pancreatic cancer development and the increased understanding of this interaction will be of potential value in designing new modalities of targeted therapy.
118 citations
TL;DR: Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis and regression in xenograft models, these benefits remain to be confirmed.
Abstract: Pancreatic cancer is the fourth leading cause of cancer related death. The difficulty in detecting pancreatic cancer at an early stage, aggressiveness and the lack of effective therapy all contribute to the high mortality. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, which is expressed in normal human tissues. It is a member of the tyrosine kinase family of growth factors receptors and is encoded by proto-oncogenes. Several studies have demonstrated that EGFR is over-expressed in pancreatic cancer. Over-expression correlates with more advanced disease, poor survival and the presence of metastases. Therefore, inhibition of the EGFR signaling pathway is an attractive therapeutic target. Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis and regression in xenograft models, these benefits remain to be confirmed. Multimodality treatment incorporating EGFR-inhibition is emerging as a novel strategy in the treatment of pancreatic cancer.
109 citations
TL;DR: The epidermal growth factor receptor/HER2 tyrosine kinase inhibitor lapatinib partially overcame trastuzumab resistance in a clinical setting, so its efficacy results and limited data regarding potential mechanisms of resistance to the drug are discussed.
Abstract: Approximately 20% of breast cancers are characterized by overexpression of human epidermal growth factor receptor 2 (HER2) protein and associated gene amplification, and the receptor tyrosine kinase is believed to play a critical role in the pathogenesis of these tumors. The development and implementation of trastuzumab, a humanized monoclonal antibody against the extracellular domain of HER2 protein, has significantly improved treatment outcomes in patients with HER2-overexpressing breast cancer. However, despite this clinical usefulness, unmet needs for better prediction of trastuzumab's response and overcoming primary and acquired resistance remain. In this review, we discuss several potential mechanisms of resistance to trastuzumab that have been closely studied over the last decade. Briefly, these mechanisms include: impaired access of trastuzumab to HER2 by expression of extracellular domain-truncated HER2 (p95 HER2) or overexpression of MUC4; alternative signaling from insulin-like growth factor-1 receptor, other epidermal growth factor receptor family members, or MET; aberrant downstream signaling caused by loss of phosphatase and tensin homologs deleted from chromosome 10 (PTEN), PIK3CA mutation, or downregulation of p27; or FCGR3A polymorphisms. In addition, we discuss potential strategies for overcoming resistance to trastuzumab. Specifically, the epidermal growth factor receptor/HER2 tyrosine kinase inhibitor lapatinib partially overcame trastuzumab resistance in a clinical setting, so its efficacy results and limited data regarding potential mechanisms of resistance to the drug are also discussed.
104 citations
TL;DR: Findings indicate that E2 regulation of the CXCL12 signaling axis is important for the E2-mediated growth effect of breast cancer cells and provide support for distinct biological functions of CXCR4 and CxCR7 and suggest that targeting CX CR4 and/or C XCR7 would have distinct molecular effects on ER-positive breast tumors.
Abstract: CXCR4 and CXCR7 are the two receptors for the chemokine CXCL12, a key mediator of the growth effect of estrogens (E2) in estrogen receptor (ER)-positive breast cancers. In this study we examined E2-regulation of the CXCL12 axis components and their involvement in the growth of breast cancer cells. CXCR4 and CXCR7 were differentially regulated by E2 which enhanced the expression of both CXCL12 and CXCR4 but repressed the expression of CXCR7. Formaldehyde-associated isolation of regulatory elements (FAIRE) revealed that E2-mediated transcriptional regulation of these genes is linked to the control of the compaction state of chromatin at their promoters. This effect could be accomplished via several distal ER-binding sites in the regions surrounding these genes, all of which are located 20-250 kb from the transcription start site. Furthermore, individual down-regulation of CXCL12, CXCR4 or CXCR7 expression as well as the inhibition of their activity significantly decreases the rate of basal cell growth. In contrast, E2-induced cell growth was differentially affected. Unlike CXCR7, the inhibition of the expression or activity of either CXCL12 or CXCR4 significantly blunted the E2-mediated stimulation of cellular growth. Besides, CXCR7 over-expression increased the basal MCF-7 cell growth rate and decreased the growth effect of E2. These findings indicate that E2 regulation of the CXCL12 signaling axis is important for the E2-mediated growth effect of breast cancer cells. These data also provide support for distinct biological functions of CXCR4 and CXCR7 and suggest that targeting CXCR4 and/or CXCR7 would have distinct molecular effects on ER-positive breast tumors.
102 citations
TL;DR: A review of currently known enterocyte‐targeted growth factors, their mechanisms of action, and their potential therapeutic utility in inflammatory bowel disease found several growth factors are therapeutic candidates in IBD.
Abstract: Background:
A key feature of inflammatory bowel disease (IBD) is impaired epithelial repair. Human growth factors comprise an array of signaling molecules that lead to ligand-specific signal transduction. Their downstream effects are associated with several cellular functions including epithelial healing in response to injury. Several studies have described specific growth factor deficiencies in patients with IBD, implicating their role in disease pathophysiology. The aim of this review was to describe currently known enterocyte-targeted growth factors, their mechanisms of action, and their potential therapeutic utility.
Methods:
The National Library of Medicine (http://www.pubmed.gov) and meeting abstracts were searched using the following terms: growth factor, intestine, colon, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis, animal model, transforming growth factor, bone morphogenetic protein, activins, growth hormone, fibroblast growth factor, epidermal growth factor (EGF), keratinocyte growth factor (KGF), glucagon-like peptide II, granulocyte macrophage colony–stimulating factor (GM-CSF), granulocyte colony–stimulating factor (G-CSF), vascular endothelial growth factor (VEGF) inhibitors, and trefoil factors.
Results:
Several growth factors are therapeutic candidates in IBD. Growth hormone, KGF, EGF, teduglutide, GM-CSF/G-CSF have entered early clinical trials, whereas others are currently in preclinical evaluation.
Conclusions:
There are several growth factors responsible for epithelial repair. Preliminary studies using recombinant growth factors seem promising in IBD preclinical and clinical trials. (Inflamm Bowel Dis 2011;)
TL;DR: All methods used to assess EGFR expression are critically analyzed and insights into the use of inhibitors of EGFR for treatment of cervical cancer are discussed.
TL;DR: The characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy and enhanced in vivo anti-tumor efficacy over the parental mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model are reported.
Abstract: The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in preclinical models. Here, we report the characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy. The BsAb molecule (EI-04), constructed with a stability-engineered single chain variable fragment (scFv) against IGF-1R attached to the carboxyl-terminus of an IgG against EGFR, displays favorable biophysical properties for biopharmaceutical development. Biochemically, EI-04 bound to human EGFR and IGF-1R with sub nanomolar affinity, co-engaged the two receptors simultaneously, and blocked the binding of their respective ligands with similar potency compared to the parental monoclonal antibodies (mAbs). In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs. EI-04, likely due to its tetravalent bispecific format, exhibited high avidity binding to BxPC3 tumor cells co-expressing EGFR and IGF-1R, and consequently improved potency at inhibiting IGF-driven cell growth over the mAb combination. Importantly, EI-04 demonstrated enhanced in vivo anti-tumor efficacy over the parental mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model. Our data support the clinical investigation of EI-04 as a superior cancer therapeutic in treating EGFR and IGF-1R pathway responsive tumors.
TL;DR: This review focuses on the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.
Abstract: One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.
TL;DR: Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylated, cell proliferation, and increased invasion.
Abstract: Background
Epidermal growth factor receptor (EGFR) is co-activated by the μ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists co-activate EGFR, resulting in growth- and survival-promoting signaling.
Journal Article•
TL;DR: The EGFR's evolving role as a prognostic and predictive biomarker in colon cancer is discussed and the efficacy of both anti-EGFR MAbs and their predictive biomarkers have taken colon cancer treatment another step closer towards the goal of tailored cancer therapy.
Abstract: The epidermal growth factor receptor is a member of the receptor tyrosine kinase family whose members play a critical role in oncogenesis. In particular, EGFR has been shown to participate in colon cancer development. Due to its role in the progression of colon cancer, EGFR has become an attractive target for therapy and two different classes of biologic agents have been evaluated: the EGFR monoclonal antibodies and the tyrosine kinase inhibitors. These two groups of agents differ in the specific molecular site which they target on the EGFR and in their efficacy in the treatment of colon cancer. This review will discuss the EGFR's evolving role as a prognostic and predictive biomarker in colon cancer. Once thought to be an inherent predictive factor for anti-EGFR monoclonal antibodies (MAbs) the EGFR has been replaced by KRAS and to some extent BRAF. The efficacy of both anti-EGFR MAbs, cetuximab and panitumumab, has been clearly demonstrated to depend upon the KRAS mutational status. The anti-EGFR monoclonal antibodies and their predictive biomarkers have taken colon cancer treatment another step closer towards the goal of tailored cancer therapy.
TL;DR: The focus of the present review is on the structural characteristics of proteins that belong to the V EGF family and on signal‐transduction pathways that become initiated via the VEGF receptors.
Abstract: The cystine-knot motif, made up of three intertwined disulfide bridges, is a unique feature of several toxins, cyclotides and growth factors, and occurs in a variety of species, including fungi, insects, molluscs and mammals. Growth factor molecules containing the cystine-knot motif serve as ligands for a diverse range of receptors and play an important role in extracellular signalling. This superfamily of polypeptides comprises several homodimeric and heterodimeric molecules that are central characters in both health and disease. Amongst these molecules are a group of proteins that belong to the vascular endothelial growth factor (VEGF) subfamily. The members of this family are known angiogenic factors that regulate processes leading to blood vessel formation in physiological and pathological conditions. The focus of the present review is on the structural characteristics of proteins that belong to the VEGF family and on signal-transduction pathways that become initiated via the VEGF receptors.
TL;DR: Next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members and drug combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance.
TL;DR: An externally regulated delivery model that permits temporal separation of multiple angiogenic factors was used for the delivery of basic fibroblast growth factor and platelet-derived growth factor, and was able to induce red blood cell-filled neovessels, suggesting integration of angiogenesis with the existing vasculature.
Abstract: An externally regulated delivery model that permits temporal separation of multiple angiogenic factors was used for the delivery of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). While bFGF plays a significant role in the sprouting of new capillaries, PDGF plays a role in the recruitment of mural cells, which stabilize neovessels. However, these two factors have been shown to inhibit each other, when presented together. Using the externally regulated model, sequential delivery of bFGF and PDGF led to not only increased endothelial cell migration, but also endothelial cell and vascular pericyte colocalization. More importantly, this delivery strategy was able to induce red blood cell-filled neovessels, suggesting integration of angiogenesis with the existing vasculature.
TL;DR: E7080 does not significantly affect tumor cell proliferation but can inhibit their migration and invasion at concentrations that both inhibit its known targets and are achievable clinically.
Abstract: E7080 is an orally active multi-targeted kinase inhibitor whose targets include vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptors (PDGFR). It has been shown to inhibit tumor angiogenesis by targeting endothelial cells. A number of the targets of E7080 are also expressed on tumor cells and here we have looked at the direct effects of E7080 on tumor cell behavior. Using a panel of human tumor cell lines we determined the effect of E7080 on cell proliferation, migration and invasion. Inhibition of FGFR and PDGFR signaling in the cells was measured. E7080 had little effect on tumor cell proliferation. However, it blocked migration and invasion at concentrations that inhibited FGFR and PDGFR signaling. Knock-down of PDGFR-β in U2OS osteosarcoma cells also inhibited cell migration which, could not be further inhibited in the presence of E7080. Furthermore, E7080 could not inhibit the migration of a PDGFR negative cell line. E7080 does not significantly affect tumor cell proliferation but can inhibit their migration and invasion at concentrations that both inhibit its known targets and are achievable clinically.
TL;DR: The data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells.
TL;DR: It is found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway, suggesting an important signaling role of DPP 9 in the regulation of survival and proliferation pathways.
Abstract: Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathway-specific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways. Mol Cancer Res; 9(7); 948–59. ©2011 AACR.
TL;DR: It is proposed that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction.
Abstract: Introduction
Women who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC.
TL;DR: Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma
Abstract: Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma
TL;DR: An important role of different growth factors in control of different ovarian functions—ovarian cell proliferation, apoptosis, folliculogenesis, luteogenesis, oogenesis, release of hormones, response to upstream hormonal regulators, fertility and, in some cases, in development of ovarian disorders is demonstrated.
Abstract: The present review demonstrates an important role of different growth factors (of insulin-like growth factors, epidermal growth factors, vascular endothelial growth factor, thrombopoietin, erytropoietin, hepatocyte growth factor, and growth factors of Hedgehog, Wnt and Notch families) in control of different ovarian functions--ovarian cell proliferation, apoptosis, folliculogenesis, luteogenesis, oogenesis, release of hormones, response to upstream hormonal regulators, fertility and, in some cases, in development of ovarian disorders. The possibility of practical application of these growth factors for characterization, prediction, and regulation the ovarian state is demonstrated.
TL;DR: The results suggest that EP3 receptors may contribute to tumor cell metastasis by increasing cellular migration through the up-regulation of VEGFR-1 signaling.
TL;DR: The ability of IGFBP-3 to modulate signalling pathways of nuclear hormone and growth factor receptors, as well as novel receptors, is believed to play a role both in normal physiology and in disease.
Abstract: Although the insulin-like growth factor (IGF) system is essential for normal growth and development, its dysregulation has been implicated in a range of pathological states. The peptide growth factors IGF-I and IGF-II exert their effects by binding to cell-surface heterotetrameric tyrosine kinase receptors and activating multiple intracellular signalling cascades, leading to changes in the expression of proteins essential for cell proliferation, survival and differentiation. The IGF system comprises multiple ligands, receptors and high-affinity IGF binding proteins (IGFBPs), with added complexity arising from crosstalk between its receptors and other key growth-regulatory pathways such as those activated by steroid hormones, integrins and other receptor tyrosine kinases. The IGFBPs are also increasingly recognised for their intrinsic growth-regulatory activity, and the ability of IGFBP-3 to modulate signalling pathways of nuclear hormone and growth factor receptors, as well as novel receptors, is believed to play a role both in normal physiology and in disease.
TL;DR: It is proposed that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells.
Abstract: Platelet derived growth factor (PDGF) regulates gene transcription by binding to specific receptors. PDGF plays a critical role in oncogenesis in brain and other tumors, regulates angiogenesis, and remodels the stroma in physiologic conditions. Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells. The two PDGF ligands AA and BB affect expression of several miRs in ligand-specific manner; the most robust changes consisting of let-7d repression by PDGF-AA and miR-146b induction by PDGF-BB. Induction of miR-146b by PDGF-BB is modulated via MAPK-dependent induction of c-fos. We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target. We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas. We propose that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells.
TL;DR: This review provides a personal account of the different challenges faced 3 decades ago in this undertaking and describes how the path was influenced by the focus on a disease process and by the evolving general understanding of the molecular effectors of cell proliferation.
Abstract: A growth-promoting activity released from activated platelets, the platelet-derived growth factor, was discovered and characterized while the cellular and molecular mechanisms underlying the formation of the lesions of atherosclerosis were being investigated. This review provides a personal account of the different challenges we faced 3 decades ago in this undertaking and describes how our path was influenced by our focus on a disease process and by the evolving general understanding of the molecular effectors of cell proliferation.
TL;DR: The findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.
Abstract: Background
Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells