Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors

2006 ◽  
Vol 34 (3) ◽  
pp. 414-417 ◽  
Author(s):  
L.E. Kemp ◽  
B. Mulloy ◽  
E. Gherardi
Keyword(s):  
Growth Factors ◽  
Tissue Regeneration ◽  
Receptor Tyrosine Kinase ◽  
Heparan Sulphate ◽  
Signalling Pathways ◽  
Angiogenic Growth Factors ◽  
Scatter Factor ◽  
Hepatocyte Growth ◽  
Made In

The receptor tyrosine kinase Met and its ligand HGF/SF (hepatocyte growth factor/scatter factor) are essential in the signalling pathways required for embryogenesis and tissue regeneration. Aberrant signalling of this complex is also a feature of many tumours and appears to contribute to the growth, invasiveness and metastasis of both carcinomas and sarcomas. HGF/SF, like many other angiogenic growth factors, employs heparan sulphate as co-receptor. The role of this interaction has not been completely defined but appears to be physiologically relevant. Thus the presence of heparin increases the potency of HGF/SF in experiments with cells in culture leading to elevated downstream signalling effects and, although not vital for the Met–HGF/SF interaction, heparin or heparan sulphate is essential for the activity of certain isoforms of HGF/SF, such as NK1 and NK2. Here, we summarize the progress made in understanding the interaction between heparin and heparan sulphate and NK1, NK2 and HGF/SF and we discuss their role in HGF/SF–Met signalling.

Role of phytochemicals in the inhibition of epithelial–mesenchymal transition in cancer metastasis

2016 ◽  
Vol 7 (9) ◽  
pp. 3677-3685 ◽  
Author(s):  
Eun-Kyung Kim ◽  
Eun-Ju Choi ◽  
Trishna Debnath
Keyword(s):  
Growth Factors ◽  
Signaling Pathways ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Fibroblast Growth Factors ◽  
Fibroblast Growth ◽  
Scatter Factor ◽  
Mesenchymal Transition ◽  
Hepatocyte Growth

Epithelial–mesenchymal transition (EMT) development is controlled by several signaling pathways including Hedgehog, Wnt, fibroblast growth factors (FGF), hepatocyte growth factor/scatter factor (HGF),etc. Phytochemicals is very promising therapeutic candidate that inhibit the progression of EMT by inhibiting the signaling pathways.

Gene of the month: MET

2015 ◽  
Vol 68 (6) ◽  
pp. 405-409 ◽  
Author(s):  
Garret Skead ◽  
Dhirendra Govender
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Protein Product ◽  
Significant Progress ◽  
Invasion And Metastasis ◽  
Scatter Factor ◽  
Signal Transduction Cascade ◽  
Met Receptor Tyrosine Kinase ◽  
Key Features ◽  
Hepatocyte Growth ◽  
Made In

The MET receptor tyrosine kinase and its ligand hepatocyte growth factor/scatter factor (HGF/SF) are potential therapeutic targets in many human malignancies, making this pathway an important focus of molecular and cancer research. MET mutations have been detected in various tumours. In addition, many tumour types demonstrate MET and HGF/SF overexpression and amplification. The MET signal transduction cascade is complex, and manifests in a broad spectrum of mitogenic and morphogenic functions, affecting cell proliferation, migration, differentiation, morphology and survival. Cancer cells commandeer the physiological functions of this signalling axis to facilitate invasion and metastasis. Significant progress has been made in the development of agents that inhibit MET-HGF/SF signalling. In this article, we outline the key features of the MET gene, its protein product and the ligand HGF/SF, to provide an overview of this important signalling pathway and offer a summary of the relevant pathological and clinical directions of research.

Role of angiogenic growth factors in transplant coronary artery disease

2004 ◽  
Vol 36 (3) ◽  
pp. 184-193 ◽  
Author(s):  
Karl Lemström ◽  
Antti Nykänen ◽  
Jussi Tikkanen ◽  
Rainer Krebs ◽  
Roope Sihvola ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Growth Factors ◽  
Coronary Artery ◽  
Angiogenic Growth Factors ◽  
Artery Disease

scholarly journals Vasculogenesis and Angiogenesis: Molecular and Cellular Controls

2003 ◽  
Vol 9 (3) ◽  
pp. 239-248 ◽  
Author(s):  
N. Kubis ◽  
B.I. Levy
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Endothelial Cell Migration ◽  
Angiogenic Growth Factors ◽  
Blood Vessel Formation ◽  
Vasculogenesis And Angiogenesis ◽  
Cell Migration And Proliferation ◽  
Extracellular Proteolysis ◽  
Coagulation And Fibrinolysis

Angiogenesis, defined as a new blood vessel formation from a pre-existing vessel, is initiated by angiogenic growth factors and their receptors that induce endothelial cell migration and proliferation. Extracellular proteolysis is essential for deassembly and reassembly of endothelial cells to their environmental matrix. The aim of this review is to update data on the role of the coagulation and fibrinolysis system, metalloproteinases and adhesion molecules during this step of angiogenesis.

scholarly journals Immunology and Genetic of Preeclampsia

2006 ◽  
Vol 13 (2-4) ◽  
pp. 197-201 ◽  
Author(s):  
Norma C. Serrano
Keyword(s):  
Developing Countries ◽  
Growth Factors ◽  
Fetal Death ◽  
Preventive Strategies ◽  
Angiogenic Growth Factors ◽  
Third Trimester ◽  
Maternal Circulation ◽  
Familial Predisposition ◽  
The Third

Preeclampsia is a disease characterized by hypertension and proteinuria in the third trimester of pregnancy. Preeclampsia is a major cause of maternal mortality, and fetal death, especially in developing countries, but its aetiology remains unclear. Key findings support a causal role of superficial placentation driven by immune mal maladaptation, which then lead to reduced concentrations of angiogenic growth factors and to an increase in placental debris in the maternal circulation resulting in a maternal inflammatory response. Epidemiological research has consistently demonstrated a substantial familial predisposition to preeclampsia. Unfortunately, the conquest of the genes explaining such a individual susceptibility has been proved to be a hard task. However, genetics will also inform us about causality of environmental factors, and then serve as a tool to prioritize therapeutic targets for preventive strategies.

Role of different aberrant cell signalling pathways prevalent in acute lymphoblastic leukemia

Biologia ◽  
2014 ◽  
Vol 69 (9) ◽  
Author(s):  
Priya Gopal ◽  
Mausumi Paul ◽  
Santanu Paul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Cell Signalling ◽  
Signalling Pathways ◽  
Survival Ratio ◽  
Functional Abnormality ◽  
Important Progress ◽  
Made In

AbstractAcute lymphoblastic leukemia (ALL) is one of the major forms of leukemia that affects mostly adolescent individuals. The main cause of the development of ALL is not known though several important signal transduction pathways have been reported with functional abnormality in all the cases. Crucial signalling pathways reported in ALL include PI3K/Akt, Notch, Wnt, mTOR, JaK/Stat, etc. Over the past several decades important progress has been made in the management of ALL, however, relapses and post therapy survival ratio has not improved much. This brings the need for understanding the biology and mechanism involved in ALL occurrences and find new molecular targets for better treatment options and risk-adapted therapies to improve the outcome of ALL patients.

BPC 157 and Standard Angiogenic Growth Factors. Gastrointestinal Tract Healing, Lessons from Tendon, Ligament, Muscle and Bone Healing

2018 ◽  
Vol 24 (18) ◽  
pp. 1972-1989 ◽  
Author(s):  
Sven Seiwerth ◽  
Rudolf Rucman ◽  
Branko Turkovic ◽  
Marko Sever ◽  
Robert Klicek ◽  
...  
Keyword(s):  
Growth Factors ◽  
Gastrointestinal Tract ◽  
Bone Healing ◽  
Angiogenic Growth Factors ◽  
Chronic Injury ◽  
Bpc 157 ◽  
Beneficial Effects ◽  
Pathophysiological Role

Commonly, the angiogenic growth factors signify healing. However, gastrointestinal ulceration is still poorly understood particularly with respect to a general pharmacological/pathophysiological role of various angiogenic growth factors implemented in growth factors wound healing concept. Thereby, we focused on the stable gastric pentadecapeptide BPC 157, a peptide given always alone vs. standard peptidergic angiogenic growth factors (EGF, FGF, VEGF), and numerous carriers. Further, we reviewed how the gastrointestinal tract healing could be generally perceived (i) in terms of angiogenic growth factors, and/or (ii) through the healing of extragastrointestinal tissues healing, such as tendon, ligament, muscle and bone, and vice versa. Respected were the beneficial effects obtained with free peptides or peptides with different carriers; EGF, FGF, VEGF, and BPC 157, their presentation along with injuries, and a healing commonality, providing their implementation in both gastrointestinal ulcer healing and tendon, ligament, muscle and bone healing. Only BPC 157 was consistently effective in all of the models of acute/chronic injury of esophagus, stomach, duodenum and lower gastrointestinal tract, intraperitoneally, per-orally or locally. Unlike bFGF-, EGF-, VEGF-gastrointestinal tract studies demonstrating improved healing, most of the studies on tendon, muscle and bone injuries provide evidence of their (increased) presentation along with the various procedures used to produce beneficial effects, compared to fewer studies in vitro, while in vivo healing has a limited number of studies, commonly limited to local application, diverse healing evidence with diverse carriers and delivery systems. Contrary to this, BPC 157 - using same regimens like in gastrointestinal healing studies - improves tendon, ligament and bone healing, accurately implementing its own angiogenic effect in the healing. Thus, we claim that just BPC 157 represents in practice a pharmacological and pathophysiological role of various peptidergic growth factors.

Integrin β7-Mediated Regulation of Multiple Myeloma Cell Adhesion, Migration and Survival.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 949-949
Author(s):  
Paola Neri ◽  
Li Ren ◽  
Kathy Gratton ◽  
Alex Klimowicz ◽  
Adnan Mansoor ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factors ◽  
Cell Lines ◽  
Function Analysis ◽  
Consensus Sequence ◽  
Gene Array ◽  
Signalling Pathways ◽  
High Dose ◽  
Target Area

Abstract Abstract 949 Background: Integrin β7 (ITGB7) mRNA is detected in primary myeloma (MM) cells and its presence was correlated with maf gene activation. However, little is known about the role ITGB7 plays in MM. Methods and results: We have determined the expression of ITGB7 by flow cytometry in a large library of human MM cell lines and found it to be universily expressed, albeit at different levels. Similarly ITGB7 mRNA was detected by qRT-PCR in 25/27 samples of primary MM CD138+ cells. In order to better investigate the role of ITGB7 in MM adhesion, migration and survival we performed a loss-of-function analysis using the shRNA lentivirus system. Lentiviral transduction particles with validated ITGB7 shRNA, were transduced into three different MM cell lines (MM1S, INA-6 and H929) establishing stable clones with silenced ITGB7. Using adhesion assays we have demonstrated that ITGB7silenced cells are 40-50% less adherent to fibronectin (FN), E-cadherin (E-CDH) and BMSCs coated plates when compared to ITGB7positive cells (scrambeled shRNA), confirming the role ITGB7 in MM cell adhesion to stromal elements. In a transwell migration assay, ITGB7 silencing abrogated MM cells migration in response to SDF-1 gradient implicating ITGB7 in MM cells migration. Next, we investigated whether ITGB7 conferred a survival benefit to MM cells. By MTT assay ITGB7silenced cell are more sensitive to the cytotoxic effect of Bortezomib and Melphalan when cultured on regular plate and/or in the presence of FN and E-CDH, suggesting a role for ITGB7 in conferring drug resistance to MM cells through cell-adhesion dependent and independent mechanisms. Mechanistic studies have shown that ITGB7silenced cells have reduced NF-kB activity with reduced NFkB-p65 binding to the related consensus sequence and decreased nuclear phospho-p65 translocation was confirmed by immunofluorescence staining. In ELISA based assay ITGB7silenced cells co-cultured with BMSCs produced less cytokines and growth factors (VEGF, IL-6, TNF, IL-1, SDF1α) compared to ITGB7positive/BMSCs co-cultures confirming the role of ITGB7 in mediating MM cells intereaction with BMSCs altering the cytokines and growth factors produced by stromal cells. In order to investigate the signalling pathways downstream of ITGB7, ITGB7positive and ITGB7silenced INA-6 and MM1S cells were added into human FN coated plates and total RNA extracted and submitted to gene array profiling using the U133 Plus 2.0 Array. Several NF-kB regulated genes (TNF-α2, syndecan 4, IL-6, IL-8, CDK-6, Max) were downregulated and pathway analysis (Ingenuity Systems Software) identified several MM relevant pathways to be modulated by ITGB7 silencing; among them p53, integrin, IGF-1, IL-6 and VEGF signaling as well as cell cycle, apoptosis and the Wnt/β-catenin signalling pathways. Based on the in vitro data, we next investigated in vivo the effect of ITGB7 silencing on engraftment and homing of MM to bone marrow (BM), using a human plasmacytoma xenograft scid mouse model. ITGB7silenced cells grew mainly locally at the subcutaneous implantation site with delayed engraftment into the BM while ITGB7positive cells homed mostly into the BM, as indicated by the number of human CD138+ cells counted on femoral BM sections (14% in ITGB7positive vs. 4% in ITGB7silenced). In addition, tumor vessels density within the xenografted tumors, as assessed by CD31 staining, was significantly reduced in ITGB7silenced compared to ITGB7positive tumors (CD31 target area %: 4.1 vs 7.7 respectively). Lastly using myeloma tissue microarray (TMA) we have correlated ITGB7 expression with a significantly worse survival outcomes post high dose therapy and stem cell transplantation with a mTTP of 0.9 years in ITGB7 positive patients versus 2.6 years in negative cases (p<0.005). Conclusions: Taken together our results support a role for ITGB7 in MM cells migration, homing and survival and pave the way for a novel therapeutic approach targeting this molecule. Disclosures: Bahlis: Celgene: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau.

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