scholarly journals Expression of Hepatocyte Growth Factor and the Proto-oncogenic Receptor c-Met in Canine Osteosarcoma

2009 ◽  
Vol 46 (5) ◽  
pp. 869-877 ◽  
Author(s):  
H. Fieten ◽  
B. Spee ◽  
J. IJzer ◽  
M. J. Kik ◽  
L. C. Penning ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Survival Time ◽  
Receptor Activation ◽  
Disease Free Interval ◽  
Canine Osteosarcoma ◽  
Free Interval ◽  
Hepatocyte Growth ◽  
Disease Free

Hepatocyte growth factor (HGF) and the proto-oncogenic receptor c-Met are implicated in growth, invasion, and metastasis in human cancer. Little information is available on the expression and role of both gene products in canine osteosarcoma. We hypothesized that the expression of c-Met is associated with malignant histologic characteristics, a short survival time, and a reduced disease-free interval in canine osteosarcoma. Quantitative real-time polymerase chain reaction was used to analyze the messenger RNA (mRNA) expression of both HGF and c-Met in 59 canine osteosarcoma samples. The relationship between HGF and c-Met expression, patient outcome, and histologic characteristics of the tumor were studied. Western blot analysis was performed to investigate the presence of active HGF protein. The expression pattern of c-Met in 16 slides of canine osteosarcoma was identified by immunohistochemistry. Coexpression of HGF and c-Met mRNA in all canine osteosarcoma samples suggested autocrine or paracrine receptor activation. A significant, moderately positive correlation was found between c-Met and HGF mRNA expression. c-Met mRNA expression was not associated with survival time or disease-free interval. Expression of c-Met was significantly associated with metastasis via the lymphogenic route. Immunolabeling with c-Met revealed a cytoplasmic staining pattern in all osteosarcoma cell types. In this study, c-Met mRNA expression in canine osteosarcoma was found to be of no influence on survival time and disease-free interval. Further studies are necessary to confirm the involvement of the c-Met pathway in the lymphogenic route of metastasis.

Hepatocyte Growth Factor and Macrophage-stimulating Protein “Hinge” Analogs to Treat Pancreatic Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 782-795
Author(s):  
John W. Wright ◽  
Kevin J. Church ◽  
Joseph W. Harding
Keyword(s):  
Pancreatic Cancer ◽  
Signal Transduction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tumor Growth ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Met Receptor ◽  
Macrophage Stimulating Protein ◽  
Hepatocyte Growth

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

Insights into the structure of hepatocyte growth factor/scatter factor (HGF/SF) and implications for receptor activation

FEBS Letters ◽  
1998 ◽  
Vol 430 (1-2) ◽  
pp. 126-129 ◽  
Author(s):  
Dimitri Y Chirgadze ◽  
Jonathan Hepple ◽  
R.Andrew Byrd ◽  
R Sowdhamini ◽  
Tom L Blundell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Receptor Activation ◽  
Scatter Factor ◽  
Hepatocyte Growth

Effects of hepatocyte growth factor on the expression of matrix metalloproteinases and their tissue inhibitors during the endometrial cancer invasion in a three-dimensional coculture

2003 ◽  
Vol 13 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Y.-H. Park ◽  
H.-S. Ryu ◽  
D.-S. Choi ◽  
K.-H. Chang ◽  
D.-W. Park ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stromal Cells ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Hepatocyte Growth

Matrix metalloproteinase (MMP)-2 and -9 are secreted and translocated from endometrial stromal cells to HEC-1 A cells in a steroid-dependent manner. We investigated the paracrine effect of hepatocyte growth factor (HGF) on MMPs and metalloproteinase tissue inhibitor (TIMP) expression in stromal and endometrial cancer cells, and correlated with cancer cell invasiveness in three-dimensional (3D) coculture. The 3D coculture of endometrial stromal and cancer cell lines (HEC-1 A, HEC-IB, or KLE) were maintained in the presence or absence of HGF. The expression of MMP-2 and -9, MT1-MMP, TIMP-1 and -2 were examined by RT-PCR and zymography. Under the same conditions, invasion of the cancer cells was quantified by Boyden's chamber assay. HGF strongly induced MMP-9 mRNA expression in stromal cells, but had little effect on MMP-2 mRNA. MT1-MMP mRNA was detected only in KLE and stromal cells, which was also increased by HGF. TIMP-1 and -2 mRNAs was ubiquitous with no dependence on HGF. Zymographic analysis of MMPs showed that activation of MMP-2 and -9 was enhanced by HGF. A significant increase in invasion of all three cancer cells with HGF was observed. The effect of HGF on the invasiveness of 3D cocultured endometrial cancer cells and stromal cells appears to be due to induction of MMP-9 mRNA expression in stromal cells and /or increased activation of MMP-2 and MMP-9 by proteolytic digestion.

Maintenance treatment in relapsed canine lymphoma after a short L-CHOP protocol

2021 ◽  
Vol 49 (03) ◽  
pp. 185-194
Author(s):  
Karin Troedson ◽  
Nataliia Ignatenko ◽  
Csilla Fejos ◽  
Yury Zablotski ◽  
Johannes Hirschberger
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Adverse Events ◽  
Survival Time ◽  
Maintenance Treatment ◽  
Canine Lymphoma ◽  
Disease Free Interval ◽  
Overall Survival Time ◽  
Free Interval ◽  
Disease Free

Abstract Objective A number of different rescue protocols for relapsed canine multicentric large-cell lymphoma have been described. The aim of this pilot study was to evaluate the efficacy of a maintenance treatment in dogs that experienced a second complete remission after a short L-CHOP-rescue protocol. Material and methods Included in the study were dogs experiencing the first lymphoma relapse during a treatment-free period which were treated with a short L-CHOP protocol, achieved a complete remission and were afterwards treated with a continuous maintenance phase (MP) protocol. The L-CHOP protocol consisted of weekly treatments, with at least 3 additional treatments following complete remission. Thereafter the MP protocol with 2-week treatment intervals was conducted. It consisted of alternating oral home administration of different alkylating agents and one intravenously administered cytotoxic agent of a different mechanism of action. The dogs were presented either every 4 or 6 weeks for intravenous treatment and at this time a complete blood count was performed. The durations of the first remission, disease-free interval and overall survival time were evaluated. Results A total of 20 dogs were included in the study. A median of 7 weekly applications were given before the treatment was switched to the MP protocol. During MP, 14 dogs were treated intravenously every 6 weeks and 6 dogs every 4 weeks. Haematological adverse events were mainly mild. During the L-CHOP-protocol, one septic event occurred, and 2 dogs were hospitalized due to gastrointestinal adverse events. No patient required hospitalization during the MP. Fifteen dogs completed at least one cycle in the MP and a median of 8.5 chemotherapeutic treatments were administered. The median disease-free interval was 264 days and the median overall survival time was 737 days. Conclusion and clinical relevance The protocol was generally well tolerated. Since 5 patients showed disease progression during the first cycle of the MP, dogs should ideally be evaluated for minimal residual disease before being switched to the MP. The case number in the presented study was low and the treatment relatively heterogeneous. Therefore, more dogs have to be treated with the proposed protocol before general recommendations can be made.

Hepatocyte growth factor/scatter factor enhances the thrombopoietin mRNA expression in rat hepatocytes and cirrhotic rat livers

2000 ◽  
Vol 15 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Kiyoshi Yamashita ◽  
Hitoshi Matsuoka ◽  
Toshimasa Ochiai ◽  
Ryuji Matsushita ◽  
Youko Kubuki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Rat Hepatocytes ◽  
Scatter Factor ◽  
Rat Livers ◽  
Hepatocyte Growth

scholarly journals Regulation of hepatocyte growth factor secretion by fibroblasts in patients with acute lung injury

2008 ◽  
Vol 294 (2) ◽  
pp. L334-L343 ◽  
Author(s):  
Christophe Quesnel ◽  
Sylvain Marchand-Adam ◽  
Aurélie Fabre ◽  
Joëlle Marchal-Somme ◽  
Ivan Philip ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Growth Factor ◽  
Lung Injury ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Lung Fibroblasts ◽  
Cox 2 ◽  
Hepatocyte Growth ◽  
Ventilated Patients

The mechanisms of pulmonary repair in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are poorly known. Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are key factors involved in alveolar epithelial repair, present in the bronchoalveolar lavage fluid (BALF) from patients with ALI/ARDS. The role of BALF mediators in their production remains to be determined. We evaluated the overall effect of BALF from 52 patients (27 ventilated patients with ALI/ARDS, 10 ventilated patients without ALI, and 15 nonventilated control patients) on HGF and KGF synthesis by lung fibroblasts. Fibroblasts were cultured in the presence of BALF. HGF and KGF protein secretion was measured using ELISA, and mRNA expression was evaluated using quantitative real-time RT-PCR. Only BALF from ALI/ARDS patients upregulated both HGF and KGF mRNA expression and protein synthesis (+271 and +146% for HGF and KGF, respectively). BALF-induced HGF synthesis from ALI/ARDS patients was higher than that from ventilated patients without ALI ( P < 0.05). HGF secretion was correlated with BALF IL-1β levels (rho = 0.62, P < 0.001) and BALF IL-1β/IL-1 receptor antagonist ratio (rho = 0.54, P < 0.007) in the ALI/ARDS group. An anti-IL-1β antibody partially (>50%) inhibited the BALF-induced HGF and PGE2 secretion, whereas NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, completely inhibited it. Anti-IL-1β antibodies as well as NS-398 reversed the COX-2 upregulation induced by BALF. Therefore, IL-1β is a main BALF mediator involved in HGF secretion, which is mediated through a PGE2/COX-2-dependent mechanism. BALF mediators may participate in vivo in the production of HGF and KGF by lung fibroblasts during ALI/ARDS.

scholarly journals A Natural Hepatocyte Growth Factor/Scatter Factor Autocrine Loop in Myoblast Cells and the Effect of the Constitutive Met Kinase Activation on Myogenic Differentiation

1997 ◽  
Vol 137 (5) ◽  
pp. 1057-1068 ◽  
Author(s):  
Sergio Anastasi ◽  
Silvia Giordano ◽  
Olga Sthandier ◽  
Giovanna Gambarotta ◽  
Rossella Maione ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Myogenic Differentiation ◽  
Biological Effects ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Scatter Factor ◽  
Autocrine Loop ◽  
Myoblast Cells ◽  
Hepatocyte Growth

As a rule, hepatocyte growth factor/scatter factor (HGF/SF) is produced by mesenchymal cells, while its receptor, the tyrosine kinase encoded by the met proto-oncogene, is expressed by the neighboring epithelial cells in a canonical paracrine fashion. In the present work we show that both HGF/SF and met are coexpressed by undifferentiated C2 mouse myoblasts. In growing cells, the autocrine loop is active as the receptor exhibits a constitutive phosphorylation on tyrosine that can be abrogated by exogenously added anti-HGF/SF neutralizing antibodies. The transcription of HGF/SF and met genes is downregulated when myoblasts stop proliferating and differentiate. The coexpression of HGF/SF and met genes is not exclusive to C2 cells since it has been assessed also in other myogenic cell lines and in mouse primary satellite cells, suggesting that HGF/SF could play a role in muscle development through an autocrine way. To analyze the biological effects of HGF/SF receptor activation, we stably expressed the constitutively activated receptor catalytic domain (p65tpr-met) in C2 cells. This active kinase determined profound changes in cell shape and inhibited myogenesis at both morphological and biochemical levels. Notably, a complete absence of muscle regulatory markers such as MyoD and myogenin was observed in p65tpr-met highly expressing C2 clones. We also studied the effects of the ectopic expression of human isoforms of met receptor (h-met) and of HGF/SF (h-HGF/SF) in stable transfected C2 cells. Single constitutive expression of h-met or h-HGF/SF does not alter substantially the growth and differentiation properties of the myoblast cells, probably because of a species-specific ligand–receptor interaction. A C2 clone expressing simultaneously both h-met and h-HGF/SF is able to grow in soft agar and shows a decrease in myogenic potential comparable to that promoted by p65tpr-met kinase. These data indicate that a met kinase signal released from differentiation-dependent control provides a negative stimulus for the onset of myogenic differentiation.

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