Serum Concentrations Of Hepatocyte Growth Factor Research Articles

Hepatocyte growth factor: A novel tumor marker for breast cancer.

The present study concentrates on the need for a novel tumor marker in breast carcinoma, which could be the hepatocyte growth factor (HGF). It is a fibroblast-derived growth factor which acts on cells of mainly epithelial origin, known for its mitogenic, motogenic, and morphogenic activities. The aim of this study is to correlate serum HGF levels with clinicopathological parameters of breast cancer. Forty-four consecutive patients with breast cancer diagnosed on fine-needle aspiration cytology were prospectively included and evaluated. Venous blood samples were collected before the surgery. Sera were obtained by centrifugation and stored at -20°C until assayed. The control group consisted of 38 healthy, age-matched participants. Serum concentrations of HGF were measured by the quantitative sandwich enzyme immunoassay technique and correlated with clinicopathological parameters of breast cancer. The Student's t-test was used to assess the significance of HGF in breast cancer, using SPSS statistics version 22. The mean value of circulating HGF level in breast cancer patients was 527.05 ± 214.72 pg/mL and that of control group was 297.61 ± 149.2 pg/mL, and the difference was significant (P < 0.01). With univariate analysis, patients in postmenopause (P = 0.01), with poorly differentiated tumors (P < 0.001) and distant metastasis (P < 0.01), were shown to have significantly higher serum concentrations of HGF. Furthermore, it correlated significantly with mitotic figures (P < 0.01) and nuclear pleomorphism (P = 0.008). Preoperative serum HGF is a promising tumor marker of breast cancer that could predict the prognosis of breast cancer.

Analysis of Soluble Mesenchymal-Epithelial Transition Factor and Hepatocyte Growth Factor Serum Levels in Children With Autism Spectrum Disorder

Background: Hepatocyte Growth Factor (HGF) and its receptor, Mesothelial-Epithelial Transition (cMet) factor signaling, play an essential role in controlling synaptogenesis. Objectives: Because of the vital role of HGF and Met signaling in synaptogenesis and spatial learning function of the brain’s hippocampal region, we aimed to study the HGF and soluble cMet (s-cMet) serum levels in children with different stages of Autism Spectrum Disorders (ASD). Materials &amp; Methods: A total of 189 ASD patients (mild; n=69, moderate; n=63 and severe; n=57) and 82 control were enrolled in this project. Blood samples were collected from ASD patients referred to Pediatric Neurology Clinic, 17 Shahrivar Hospital, Rasht City, Iran, and serum concentrations of s-cMet and HGF were measured by ELISA. The control children with no clinical characteristics of ASD attended routine blood tests. Results: HGF Mean±SD serum concentration in ASD patients was 239±52.02 pg/mL compared to controls which was 360.04±71.15 pg/mL (P=0.004). Also, the Mean±SD serum concentrations of HGF in mild, moderate, and severe ASD patients were 297.54±69.82, 232.81±56.41, and 189±33.25 ng/mL, respectively, compared to control, which was 360.18±57.40. Besides, the s-cMet Mean±SD serum concentrations in ASD and controls were 143.54±32.50 and 200.25±31.16 pg/mL, respectively (P=0.005). The Mean±SD serum concentrations of s-cMet in the mild, moderate, and severe ASD patients were 172.81±37.69, 129.81±45.55, and 85.18±22.95 ng/mL, respectively, as compared to the control, which was 214.54±34.17 ng/mL. Conclusion: Serum HGF and s-cMet concentration decreased in ASD patients corresponding to disease severity. Also, detecting serum HGF and s-cMet may help classify ASD.

Overexpression of Hepatocyte growth factor and its soluble receptor (s-cMet) in the serum of patients with different grades of meningioma

ObjectivesMeningiomas are the most common primary intracranial tumor. Hepatocyte growth factor (HGF) and its receptor, cMet, were shown to be involved in meningioma. This study was aimed to determine the concentration of HGF and soluble cMet (s-cMet) in the serum of patients with different grades of meningioma. MethodsNinety serum samples from different grades of meningioma patients (42 cases of grade I, 28 grade II, 20 grade III) and 51 controls were included in this study. The serum total protein concentration (TPC) was measured by a Bio-Rad protein assay and serum concentration of HGF and s-cMet by enzyme linked immunosorbent assay (ELISA). ResultsNo significant change in the serum TPC of patients was seen as compared to controls. We also showed that serum HGF and s-cMet concentration in meningioma patients was higher than in controls. The results showed that starting from grades I to III meningioma, a significant increase in HGF and s-cMet serum concentration was observed (HGF; 380 ± 57.69, 430.27 ± 48.72, 596.36 ± 104.49 pg/ml, respectively, as compared to controls which was 327.72 ± 49.68 pg/ml and for s-cMet was 274.45 ± 45.05, 314.81 ± 38.71, 433.54 ± 51.81 ng/ml, respectively, as compared to controls which was 213.72 ± 29.13 ng/ml). The results showed that a high concentration of HGF and s-cMet is associated with advanced grades of meningioma. ConclusionIt is concluded that HGF and s-cMet serum levels increased in meningioma patients and their concentration was significantly higher in more advanced grades of the disease. It is also suggested that HGF/s-cMet might be involved in the progression of meningioma.

Association of Hepatocyte Growth Factor Genetic Variation (S3735520) and Its Concentration in Autism Spectrum Disorders: A Case-control Study

Background: Hepatocyte Growth Factor (HGF) was shown to play a key role in synaptogenesis, survival, maturation, and reconstruction of neuron cells and was shown to be implicated in Autism Spectrum Disorder (ASD). Objectives: Assessing the relationship between HGF (rs3735520) gene polymorphism and its circulating levels in ASD. Materials &amp; Methods: A total of 140 ASD patients and 120 children healthy controls referred to Shahid Rajaei Hospital, Mazandaran, Iran from September 2017 to January 2019 were enrolled in the study. Genomic DNA was extracted from blood samples, HGF polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism and HGF serum concentration was measured by enzyme-linked immunosorbent assay. Statistical analysis was done by ANOVA and the Chi-square test, using χ² in MedCalc statistical software ver. 12.1.4. Results: Genotype frequencies of CC, CT, and TT in the ASD group were 25.71%, 52.86%, and 21.43%, and in controls were 26.67%, 68.33%, and 5%, respectively (P=0003) and C and T alleles frequencies in patients were 53% and 47% and in controls were 61% and 39%, respectively (P=0.046). Moreover, the Mean±SD serum HGF levels in the controls and ASD patients were 363.33±118.44 and 219.95±73.61 pg/mL, respectively (P=0.009). Furthermore, ASD patients carrying TT genotype had lower serum HGF levels than CT and TT carriers (CC, CT, and TT Mean±SD serum levels were 271.88±30.47, 217.77±33.59 and 156.33±22.72 pg/mL, respectively). Conclusion: There was a significant relationship between HGF gene polymorphism and its serum levels with ASD in an Iranian population. We also suggest that TT genotype may be associated with a decrease in HGF circulation levels in ASD.

Atherosclerosis impacts the link between hepatocyte growth factor and cognition

Background. There is a controversy about the association between Hepatocyte growth factor (HGF) and cognition. Increased serum level of HGF has been reported in patients with hypertension, peripheral arteriosclerosis and carotid atherosclerosis. Ankle-brachial index (ABI) is considered as a marker of atherosclerosis. we hypothesized that hypertension or atherosclerosis with hypertension could alter the relation between HGF serum level and cognitive function. Aim. To study HGF and cognitive function in hypertensives with and without atherosclerosis versus healthy controls. Methods. This case-control study included ninety elderly subjects attending outpatient primary care geriatric clinics. They were subdivided into 3 groups; Group A (30 normotensives with normal Ankle-brachial index (ABI) as controls, group B (30 hypertensives with normal ABI) and group C (30 hypertensives with abnormal ABI) as cases. Cognitive function was assessed by Rowland Universal Dementia Assessment Scale (RUDAS). Results. Group C had worse score in RUDAS than controls (P = 0.01). HGF was negatively correlated with ABI in group C (p = 0.007). HGF was positively associated with RUDAS score, in group A (p < 0.001), in group B; after further adjustment for systolic blood pressure (SBP) (p = 0.024) and in group C; after adjustment for ABI (p = 0.031) or ABI and SBP (p = 0.05). Conclusions. The potential beneficial link between HGF serum concentration and cognition was met in normotensive subjects with normal ABI. However, this link is halted in the presence of hypertension or atherosclerosis as assessed by ABI. Alternatively, the raised HGF serum level may be an epiphenomenon of atherosclerosis.

Serum concentrations of HGF are correlated with response to anti-PD-1 antibody therapy in patients with metastatic melanoma

BackgroundAnti-programmed cell death protein (PD)-1 antibody treatment is associated with a notable improvement in only 30%–40% of patients. Thus, a predictive and easily measured marker of the clinical benefit of anti-PD-1 antibody treatment is necessary; therefore, in this study, we focused on the serum concentration of hepatocyte growth factor (HGF). ObjectivesTo evaluate whether the serum concentration of HGF can be used as a biomarker for the clinical response to anti-PD-1 antibody therapy. MethodsThis study included 29 metastatic melanoma patients receiving nivolumab or pembrolizumab. Nine patients responded to anti-PD-1 antibody treatment, whereas the other 20 patients did not. The serum concentrations of HGF were analyzed by using ELISA. In 28 patients, immunohistochemical analysis of the HGF protein in patients’ cancer tissues was also performed. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with an anti-CD3 antibody in the presence or absence of HGF and c-MET inhibitor. The expression of perforin in CD8+ T cells were evaluated by using flow cytometry. ResultsAmong the 29 recruited patients, the non-responders displayed higher serum concentrations of HGF than the responders (P = 0.00124). Patients with low serum concentrations of HGF showed longer overall survival (N = 28, P = 0.039; HR 0.3125, 95% CI 0.1036–0.9427) and progression-free survival (N = 24, P = 0.0068; HR 0.2087, 95% CI 0.06525–0.6676) than those with high concentrations of HGF. We observed a significant correlation between the serum concentration of HGF and immunohistochemical-positive staining (P = 0.000663). In a flow cytometry analysis of PBMCs from healthy donors, HGF was found to downregulate perforin secretion. Furthermore, the addition of capmatinib, a specific inhibitor of c-MET, increased the expression of perforin in CD8+ T cells. ConclusionsHGF concentration represents a valid biomarker that can be further developed for the evaluation of anti-PD-1 therapy. Our results suggested that c-MET inhibition promotes perforin expression in CD8+ T cells. Therefore, c-MET inhibitors can activate the immune system and may play an important role in combined immunotherapy.

Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus.

Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.

Increased Serum Hepatocyte Growth Factor (HGF) Levels in Patients with Idiopathic Pulmonary Fibrosis (IPF) or Progressive Sarcoidosis

Background: Endogenous Hepatocyte Growth Factor (HGF) is required for self-repair of injured liver, kidneys and lungs. It also exerts a regenerative effect on epithelium. HGF can inhibit both the initiation and progression of lung fibrosis in Idiopathic Pulmonary Fibrosis (IPF). However available literature data on the role of HGF in sarcoidosis are scarce and conflicting. The aim of our study was to estimate and compare the serum concentrations of HGF both in patients with IPF and sarcoidosis and in healthy controls. Material and methods: In 43 patients with sarcoidosis, 17 patients with IPF and 20 healthy controls serum HGF concentrations were measured using multiplex bead based sandwich immunoassay. Results: In patients with IPF mean concentrations of HGF (1286.2 ± 238.3 pg/ml) were significantly higher than in controls (819.8 ± 61.0 pg/ml, p<0.05), but not significantly higher than in sarcoidosis patients (990.0 ± 52.2 pg/ ml). In all patients with sarcoidosis the mean levels of HGF did not differ significantly from levels obtained in control group. However, the mean levels of HGF in 18 patients with progressive sarcoidosis (1260.7 ± 83.7 pg/ml) were significantly higher (p<0.001) than in 25 patients with non-active, stable sarcoidosis (802.7 ± 34.8 pg/ml) and controls (p<0.05). Conclusion: The role of serum HGF as a potential biomarker in sarcoidosis needs further explorations to answer the question if increased HGF serum levels can predict deterioration of the disease or reflect lung epithelial injury by granulomatous inflammation.

Hepatocyte Growth Factor Inhibits Lipopolysaccharide-Induced Oxidative Stress via Epithelial Growth Factor Receptor Degradation

Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II-induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism. HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2-containing inositol 5'-phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model. The present study revealed inhibition of LPS-induced vascular cell adhesion molecule-1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2-containing inositol 5'-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease.

The levels and clinical significances of hepatocyte growth factor in the hepatic tissue and serum of hepatocellular carcinoma

Objective To investigate hepatocyte growth factor (HGF) levels in the tissue and serum of patients with chronic hepatitis, cirrhosis or hepatocellular carcinoma (HCC), and analyze the clinical significances of HGF for HCC. Method Surgical specimens from 97 patients were collected during Dec.2003 to Aug.2008 in the Third Central Hospital.The patients were prospectively enrolled and categorized into four groups:normal subjects (n=11), chronic hepatitis B or C (n=6), cirrhosis (n=20) and HCC (n= 60) including well-differentiated (n= 21), moderately differentiated (n= 23), poorly differentiated (n= 16) specimens.N0 (n=24), N1 (n=21), N2 (n=54) and N3 (n=43) were tissues respectively removed from liver at 0, 1, 2 or 3 cm beyond the margin of tumor.HGF mRNA expression in liver tissues was determined by real-time quantitative reverse transcription- (RT)-PCR.Serum HGF levels in the other cases of normal subjects (n=20), chronic hepatitis B or C (n=20), cirrhosis (n=20) and HCC (n=57) were measured by ELISA.The Kaplan-Meier method with log-rank test was employed for survival analysis.Univariate and multivariate analyses were performed to identify prognostic factors in each group. Results The HGF mRNA in normal subjects, chronic hepatitis, cirrhosis, N3, N2, N1, N0 and HCC were 0.99(0.78-1.66), 2.15(1.06-3.40), 1.78(1.18-2.73), 4.59(2.67-8.63), 3.86(2.25-6.45)，3.12(1.59-5.74), 2.92(0.88-5.99) and 0.48(0.19-1.06) respectively.The serum concentration of HGF in the normal subjects, chronic hepatitis, cirrhosis and HCC patients were (0.31±0.05), (0.65±0.07), (1.27±0.30) and （2.06±0.66） μg/L respectively.The highest level of HGF mRNA was found in N3, while the HGF mRNA expression in HCC was ［（2.14±0.52）μg/L］ lower than that not only in the non-tumor tissues, but also in the normal control (U=196.50, P=0.03).The serum concentration of HGF was significantly higher in patients with chronic hepatitis, cirrhosis or HCC than in normal subjects.The serum HGF level of HCC was bounced after hepatectomy (t=2.70, P＜0.01).On the logistic regression analysis，the tumor numbers and Child-pugh were related with the levels of the tissue HGF mRNA and serum HGF of HCC, OR were 0.15 (95%CI：0.03-0.72, P<0.05) and 0.13 (95%CI：0.27-0.89, P<0.05), respectively.Univariate analysis using the Cox proportional hazards model in the complication groups revealed that the levels of the tissue HGF mRNA and serum HGF were significant risk factors of death for HCC, OR were 0.02 (95%CI:0.00-0.52, P<0.05) and 10.01 (95%CI:1.16-86.23, P< 0.05), respectively.On the Log-rank analysis, no statistically difference in the cumulative survival was found between the two groups categorized by median (0.49) of tissue HGF mRNA 2-ΔΔCT (χ2=0.13，P=0.72). While the HCC patients were dichotomized by their the median(0.69 μg/L) of serum HGF concentration, the death risk for the patients with higher levels of HGF was increased 2.84 fold than those with lower levels (95%CI:1.03-7.92，P<0.05). Conclusion HGF mRNA expression is decreased in tumor tissues, while its level in tumor adjacent live and serum is significantly elevated and is in association with shortened postoperative survival of HCC patients.（Chin J Lab Med,2012,35:598-603） Key words: Liver neoplasms; Carcinoma，hepatocellular; Hepatocyte growth factor; Reverse transcription-quantitative polymerase chain; Enzyme-linked immunosorbent assay

Hepatocyte growth factor: Molecular biomarker and player in cardioprotection and cardiovascular regeneration

The liver possesses impressive regenerative capacities. Grafts of embryonic liver explants and liver explant-conditioned media have been shown to enhance the mitotic activity of hepatocytes. Hepatocyte growth factor (HGF), also named scatter factor (SF), has been identified as a primary candidate in promoting and regulating liver regeneration. Although initially thought to be a liver-specific mitogen, HGF was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting apoptosis, endogenous HGF may play an important role in cardioprotection as well as in the regeneration of endothelial cells and cardiomyocytes after myocardial infarction. Since serum concentration of HGF increases in the early phase of myocardial infarction and in heart failure, HGF may also play a key role as a prognostic and diagnostic biomarker of cardiovascular disease. Here we discuss the role of HGF as a biomarker and mediator in cardioprotection and cardiovascular regeneration.

Decreased Serum Hepatocyte Growth Factor (HGF) in Individuals with Bipolar Disorder Normalizes after Zinc and Anti-oxidant Therapy

Aim:To assess serum HGF concentration in individuals with bipolar disorder and investigate the efficacy of zinc therapy on these levels.Subjects and methods:Serum from 35 individuals diagnosed with bipolar disorder and 19 age and gender similar controls were tested for HGF concentration using ELISAs, and copper and zinc plasma levels using inductively-coupled plasma-mass spectrometry.Results:HGF serum levels of individuals with bipolar disorder were significantly lower than age and gender similar controls (P = 0.0021). HGF serum concentration was significantly lower in Bipolar patients pre-therapy (P = 0.0009) and HGF levels normalized post-therapy. Zinc levels in these same individuals also normalized (P = 0.0046) and patient’s perceived severity of Bipolar symptoms significantly decreased after therapy (P = 0.0003). We also found a significant direct correlation between Zinc and HGF serum concentration in the bipolar patients (P = 0.04).Discussion:These results suggest an association between low HGF levels and bipolar disorder and also demonstrate that zinc therapy may be associated with the normalization of HGF levels and decrease in severity of disease.

Decreased Serum Hepatocyte Growth Factor (HGF) in Individuals with Anxiety Increases after Zinc Therapy

Aim:To assess serum Hepatocyte Growth Factor (HGF) levels in individuals with anxiety and to test the hypothesis that there is a relationship between HGF levels and zinc therapy.Subjects and methods:Serum from 19 individuals with anxiety and 19 controls were tested for serum HGF using ELISAs. HGF serum concentration in individuals with anxiety before zinc and anti-oxidant therapy was compared to levels after therapy. Zinc and copper levels in anxiety patients, pre and post therapy, were also measured and compared.Results:Individuals with anxiety had significantly lower serum levels of HGF compared to controls (P = 0.0005). HGF concentration rose significantly (normalized) after zinc therapy (P = 0.04) and zinc levels increased significantly in these same patients (P = 0.0002).Discussion:These results suggest an association between HGF serum levels and individuals with anxiety and demonstrate that zinc therapy is associated with increasing HGF levels.

The role of serum concentration of hepatocyte growth factor in clinical monitoring of oral squamous cell carcinoma

Background and Objectives: Generally, squamous cell carcinoma has a poor prognosis due to its tendency towards local invasion and subsequent metastasis, which is mediated by multiple factors and angiogenesis. Hepatocyte growth factor (HGF) is a potent mitogen for epithelial cells that regulates cell proliferation, migration, survival tumour angiogenesis and invasiveness. The aim of presented study was to determine serum concentration of HGF in patients with oral squamous cell carcinoma before and after initial treatment.

Hepatocyte Growth Factor-Producing Multiple Myeloma (HGF myeloma) Is a Distinct Clinical Entity and Needs for Molecular Targeted Therapy.

Background and Objective: Disease control of refractory or relapsed multiple myeloma (MM) remains a therapeutic challenge. Classification of the patients in the molecular basis and development of targeted therapy are crucial to overcome the situation. We previously reported that 20–30% of MM cells produce hepatocyte growth factor (HGF), and its serum concentration was specifically elevated in symptomatic MM patients. The purpose of this study is to elucidate the clinical characteristics of HGF-producing MM (HGF myeloma) and to explore a novel therapy.Patients & Methods: Serum concentrations of HGF obtained from 76 patients with MM were measured by ELIZA. Less than 0.3μg/L was considered as a normal range. Association of serum HGF levels with various clinical parameters for disease activity was examined, including age, ISS stage, type of M protein, hemoglobin level, serum creatinine, Ca, β2M, albumin, LDH, CRP, bone marrow MM cell %, chromosomal abnormality, presence of lytic bone lesion and extramedullar plasmacytoma. Phase 2 thalidomide monotherapy was also conducted in 56 patients with refractory MM. HGF-specific competitive inhibitor, NK4 protein, was used for in vitro experiments such as growth inhibition by MTT assay, induction of apoptosis by flow cytometer and activation of intracellular signaling molecules by Western blot analysis. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was intramuscularly injected into lcr/scid-mice bearing tumors derived from HGFproducing KMS11 and 34 cells.Results:Elevated serum HGF level was significantly associated with the presence of anemia (p=0.03) and lytic bone lesion (p=0.009). Seven out of eight patients with high CRP levels without infection and five out of nine patients with extramedullar plasmacytoma also demonstrated elevated serum HGF level.Furthermore, in thalidomide monotherapy for refractory MM, increase in pre- and posttreatment serum HGF level was significant poor prognostic factors for overall survival (OS) in univariate analyses, p=0.025 and 0.01, respectively. Elevation of post-treatment HGF level was also independent poor prognostic factor for OS in multivariate analysis.We next examined the possibility of molecular targeted therapy of HGF using NK4.NK4 protein stabilized the growth of HGF-producing MM cell lines and primary bone marrow MM cells in vitro. NK4 also increased in annexin V+ apoptotic cell fraction and regulated the activation of c-Met, ERK1/2, STAT3, and AKT-1. AdCMV.NK4 significantly delayed growth of KMS 11 and 34-derived tumors in vivo. Histological examination revealed that AdCMV.NK4 induced apoptosis of the tumor cells, accompanied by a reduction in neovascularization in the tumors. AdCMV.NK4 injection prolonged survival of KMS 11 tumor-bearing mice.Conclusion: HGF myeloma is characterized by increased disease activity such as anemia, bone lesion, high CRP level and extramedullar plasmacytoma and also by shorter survival by conventional therapy including thalidomide, and it should be recognized as a distinct clinical entity. Since NK4 showed direct anti-myeloma effect as well as anti-angiogenic activity against HGF-producing MM cells, molecular targeted therapy, for example using NK4, is to be established to improve the therapeutic outcome of HGF myloma.

Bladder Cancer Cell Invasion Is Enhanced by Cross-Talk with Fibroblasts Through Hepatocyte Growth Factor

To examine the effects of fibroblast-derived humoral factors, especially hepatocyte growth factor (HGF), on the invasive potential of bladder cancer cells. Stromal cells in cancer tissue are thought to play an important role in the transformation and invasion of cancer cells. The influence of fibroblast cells (TIG-1 cells) and HGF on the invasive potential of bladder cancer cells (5637, T24, J82, HT1376, and MGHU-1 cells) was evaluated by in vitro cell invasion assay. The expression of HGF and c-Met, which is the receptor of HGF, was examined by reverse transcriptase-polymerase chain reaction. To clarify the relationship between the serum HGF level and invasive bladder cancer, we measured the serum concentrations of HGF in patients with bladder cancer without metastatic disease and normal controls, using an enzyme-linked immunosorbent assay. The in vitro cell invasion assay showed that the number of invading bladder cancer cells was significantly increased by the conditioned medium (CM) of the fibroblast cells. HGF neutralization antibody partially inhibited the enhancement of invasiveness by fibroblast CM. The CM of fibroblasts cultured with bladder cancer CM stimulated cancer cell invasion more strongly (with increased HGF secretion) than did the CM of fibroblasts cultured without bladder cancer CM. The serum HGF levels were significantly greater in patients with muscle-invasive bladder cancer (regardless of tumor size) than in patients with non-muscle-invasive bladder cancer. The present results have suggested that bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through humoral factors, including HGF. Elucidation of this mechanism could lead to novel therapeutic strategies for bladder cancer.

The significance of serum hepatocyte growth factor levels in planning follow-up of postoperative jaundice-free patients with biliary atresia

Purpose The aim of this study was to clarify the significance of serum hepatocyte growth factor (HGF), interleukin (IL)-6, and IL-1 receptor antagonist (ra) levels in the evaluation of disease status in jaundice-free survivors with biliary atresia after Kasai operation. Patients and Methods Serum concentrations of HGF, IL-6, and IL-ra were measured in 31 long-term jaundice-free patients with biliary atresia after Kasai operation and 29 controls. Patients were divided into 4 groups: group A (n = 8), normal liver function; group B (n = 9), mild liver dysfunction without portal hypertension; group C (n = 9), moderate liver dysfunction with controllable portal hypertension; and group D (n = 5), receiving liver transplantation. Results Serum IL-6 levels were significantly higher in patients than in controls. There was no difference in serum IL-6 levels among groups B, C, and D. Serum IL-1ra levels were elevated according to liver dysfunction. Serum HGF levels in group D were significantly higher than in controls and the other groups. Serum hyarulonic acid levels were positively correlated with serum levels of IL-1ra and HGF. Conclusions Elevation of serum IL-1ra and HGF levels correlated with the progression of liver fibrosis and dysfunction. In particular, serum HGF levels could be used as a predictor for requiring liver transplantation.

Prediction of lung-transplant rejection by hepatocyte growth factor

Graft rejection is a major complication of lung transplantation. No serological marker of rejection is in common use. Hepatocyte growth factor (HGF) is highly expressed in the lung and produced after acute lung injury; serum concentrations increase in inflammatory lung diseases. We investigated whether HGF could be an accurate marker for prediction of lung-graft rejection. Serum concentrations of HGF were measured by ELISA in 109 patients who had undergone lung transplantation (65 for chronic obstructive pulmonary disease; 23 for cystic fibrosis; 21 for idiopathic lung fibrosis), comparing those who had no subsequent events and those with episodes of infection or rejection, as well as in 12 healthy controls. The mean baseline serum HGF concentration was 645 ng/L (SD 259) in controls and 1358 ng/L (603) in the patients before transplantation. After transplantation the mean concentration in patients with no events was 1147 ng/L (510) compared with 1559 ng/L (323) in patients with infection (p=0.001 vs controls; change from pretransplant value not significant). Patients with rejection had significantly higher concentrations than all other groups (3972 ng/L [1463], p<0.0001). Logistic regression identified HGF as a predictor for lung graft rejection (p=0.012). After steroid treatment, HGF concentrations returned almost to the preoperative values within 3 days. HGF might be a marker for graft rejection in lung transplantation. A potential link between viral infection, mainly cytomegalovirus, and HGF, however, remains to be investigated.

Sample handling and stability of hepatocyte growth factor in blood samples.

As regards clinical studies performed on hepatocyte growth factor (HGF) during recent years, we have aimed in the present study to investigate the eventual differences in sample handling of this cytokine that might influence the results of serum concentrations. Venous blood from patients with current infectious diseases and controls was used in different sub-studies. Compared with samples separated within one hour, no significant changes in serum HGF levels were observed when whole blood stayed 4, or 24h at 6 degrees C before or 6h in room temperature after separation but HGF levels were significantly higher (P<0.01) when whole blood was kept at room temperature 4 and 24h before separation. Serum HGF was stable up to 20 freeze-thaw cycles. The serum concentrations of HGF were significantly higher than levels in the plasma (19%; P<0.05). A significant increase in serum HGF levels (12%, P<0.05) was observed after shaking the whole blood sample to a visible haemolysis, although the HGF concentration in blood cells was around half of that in serum. HGF tolerated storage at -70 degrees C for at least 4 months. We conclude that standardized methods in sample handling are important in the study of HGF concentrations in blood samples.

Review: ligands for receptor tyrosine kinases expressed in the skin as environmental factors for melanocyte development.

Skin is the major tissue where melanocytes develop, and skin keratinocytes provide the necessary micro-environment for melanocyte survival, proliferation, differentiation, and migration. In this paper, we will discuss the ligands for receptor tyrosine kinases produced as environmental cues to support melanocyte development in the skin.