Hepatocyte Growth Factor Concentrations Research Articles

Clinical Correlations and Prognostic Relevance of Tissue Angiogenic Factors in Patients with Gastric Cancer

AimsTo evaluate the relationship between vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in gastric cancer tissue and clinicopathological features and to determine whether these factors were correlated with survival. Materials and methodsWe analysed tissue samples from 58 patients with gastric cancer and used 24 normal gastric mucosae as controls. Tissue levels of VEGF and HGF were measured in tissue extracts by enzyme-linked immunosorbent assay. ResultsHGF and VEGF levels were significantly higher in gastric cancer tissue than in matched normal gastric mucosa. VEGF levels were significantly increased in cancer tissue from cases involving lymphatic invasion. HGF levels were significantly increased according to the disease stage. Patients with high levels of VEGF or HGF showed significantly worse survival rates than patients with low levels. Using multivariate analysis, a high level of VEGF or HGF was an independent factor predicting poor survival. ConclusionsIntratumoral levels of HGF and VEGF are an important prognostic determinant in gastric cancer. The current findings suggest that high concentrations of HGF and VEGF may induce aggressive tumour growth and metastasis.

Abstract 9803: Relation of Vascular Growth Factors with CT-Derived Measures of Body Fat Distribution: The Framingham Heart Study

Background: Obesity is associated with cardiometabolic risk. However, the localization of excess body fat impacts on the accompanying morbidity. Given that angiogenesis is a key feature of adipogenesis, and that angiogenic factors correlate with cardiovascular risk, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the pathogenicity of regional fat depots. Methods and Results: We assessed relationships of four body fat compartments (visceral adipose tissue - VAT, subcutaneous adipose tissue - SAT, thoracic periaortic fat, pericardial fat) derived from computed tomography with serum levels of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (sFlt-1), hepatocyte growth factor (HGF), angiopoietin-2 and its soluble receptor (sTie-2) using multivariable linear regression models in 1806 Framingham Third Generation participants (mean age 44.9 years, 44.5% women). VAT, SAT and periaortic fat were positively associated with VEGF (p=0.004, p<0.0001 and p=0.03, respectively). HGF was positively associated with all assessed fat depots (all p<0.0001). VAT and periaortic fat were weakly associated with sTie-2 (p=0.01 and p=0.03). For HGF, we observed effect modification by sex: associations of VAT, pericardial and periaortic fat with HGF were stronger in women than in men; in women, higher VAT and higher periaortic fat were jointly associated with higher HGF concentrations (p=0.02 and p=0.05, respectively). In women within the highest tertile of VAT, HGF levels increased with higher periaortic fat (p=0.0005; Figure ). Conclusions: We observed associations of several body fat compartments with circulating VEGF and HGF levels. In women, high VAT and high periaortic fat were jointly associated with greater HGF levels. Whether this finding will translate to elevated morbidity in this group warrants further evaluation.

Concentrations of Metalloproteinased-9 (MMP-9), Metalloproteinases -1 and-2 Tissue Inhibitors (TIMP-1, TIMP-2), Tumor Necrosis Factor-α (TNF-α), Hepatocyte Growth Factor (HGF), Dickkopf Related Proten 1 (DKK-1) and Emmprin (CD147) Expression Are Increased in Patients with Myeloma Multiplex and MMP-9 Correlates with advanced Stage of Disease

Abstract 5069 Introduction.Metalloproteinases (MMP) belong to the group of metallodependent proteolitic enzymes included into endopeptidases being characteristic for the ability of extracelullar matrix degradation. Gelatinases: A(MMP-2) and B (MMP-9) take part in neoplasms metastatic process. MMP activity is controlled both by their tissue inhibitors (TIMP) and activator (emmprin). Multiple myeloma (MM) is a lymphocytes B proliferative disease which is accompanied by osteolytic lesions and extramedullar spread. There are few reports concerning the assessment of MMP-2, MMP-9, TIMP-1, TIMP-2, TNF-α, HGF, DKK-1 concentrations as well as emmprin expression on bone marrow mesenchymal stem cells (BMSC) in patients suffering from multiple myeloma. Aim.The goal of the study was to assess MMP-2, MMP-9, TIMP-1,TIMP-2, TNF-α, HGF, DKK-1 concentrations in marrow plasma, in culture supernatant as well as emmprin expression on BMSC in multiple myeloma patients. The survey also comprised metalloproteinases, their inhibitors and cytokines influence on myeloma development and progress and included the trial whether these parameters are related to clinical stage of myeloma. Patients and methods.Forty patients were enrolled in the study: 18 males and 22 females aged 48–81 years (mean age-52.4 years) with de novo diagnosed multiple myeloma. According to ISS (International Staging System) 7 patients were at stage I, 19 patients were at stage II and 14 patients were at stage III. Control group consisted of 11 healthy persons matched with age and sex. Bone marrow was collected before the treatment. Bone marrow mesenchymal stem cells (BMSCs) revealing antigen CD166 expression were derived in incubation process on Mesencult culture. Concentrations: MMP-2 and TIMP-2, MMP-9, TIMP-1, TNF-α, HGF and DKK-1 were measured in marrow plasma and culture supernatant with ELISA test. Emmprin expression on CD166+ cells was assessed by FACS analysis. Results.Mean concentrations of MMP-9, TIMP-1 and TIMP-2 in both marrow plasma and culture supernatant were significantly higher in multiple myeloma patients in comparison with control group. Mean concentration of TNF-α, HGF and DKK-1 assessed in culture supernatant were significantly higher in patients than in control group. In turn, MMP-2 mean concentration in marrow plasma did not differ significantly between patients and control groups. MMP-9/TIMP-1 ratio for marrow plasma and supernatant was significantly higher in MM group. MMP-2/TIMP-2 ratio for culture supernatant was higher in patients in comparison with healthy persons. Besides, in patients at the higher stage of the disease progress (II+III), MMP-9 concentration estimated in marrow plasma was higher than in patients placed at the disease advance low stage (I). CD147 expression on BMSC cells of myeloma patients was significantly higher than the one on BMSC collected from healthy persons. It also correlated with MMP-2 and TIMP-2 concentrations and MMP-2/TIMP-2 ratio in culture supernatant. Conclusions.Concentrations of MMP-9, MMP-2, TIMP-1, TIMP-2, TNF-α, HGF and DKK-1 and emmprin expression are increased in myeloma patients and concentration of MMP-9 correlates with advanced stage of disease. Disclosures:No relevant conflicts of interest to declare.

Adipose tissue quantity and composition contribute to adipokine concentrations in the subclavian vein and the inferior mesenteric vein

Adipose tissue dysfunction is associated with inflammation, type 2 diabetes mellitus and vascular diseases. Visceral adipose tissue (VAT)-derived adipokines, which are released in the portal circulation may influence liver metabolism. (1) To estimate the contribution of VAT and subcutaneous adipose tissue (SAT) on adipokine levels by measuring differences in adipokine concentrations between the portal draining inferior mesenteric vein and the subclavian vein. (2) To determine the relation of both VAT and SAT quantity and composition to mesenteric and systemic concentrations of adipokines. Cross-sectional cohort study. A total of 32 patients undergoing abdominal aortic surgery. A panel of 18 adipokines was measured in perioperatively obtained blood samples from the subclavian vein and the inferior mesenteric vein. Adipocyte size, macrophage infiltration and capillary density were measured in subcutaneous and mesenteric adipose tissue biopsies; SAT and VAT areas were measured on computed tomography images. Serum interferon-γ-inducible protein 10 (IP-10) and hepatocyte growth factor (HGF) concentrations were significantly higher in the inferior mesenteric vein vs the subclavian vein. SAT area (β -18; 95% confidence interval (CI) -35 to -2), subcutaneous adipocyte size (β -488; 95% CI -938 to -38) and SAT macrophages quantity (β -1439; 95% CI -2387 to -491) were negatively associated with adiponectin levels in the systemic circulation. SAT area was related to systemic concentrations of leptin. Mesenteric adiponectin concentrations were related to VAT area (β -20; 95% CI -35 to -5) and visceral adipocyte size (β -1076; 95% CI -1624 to -527). VAT area, adipocyte size and capillary density were related to systemic adiponectin concentrations. SAT and VAT quantities as well as morphologic characteristics of both adipose tissue depots are related to systemic and mesenteric adipokine concentrations. There were no differences in adipokine concentrations between the mesenteric and subclavian vein, except for higher IP-10 and HGF concentrations in the inferior mesenteric vein, indicating a possible contribution of VAT to IP-10 and HGF levels.

Effects of erythropoietin on angiogenesis after myocardial infarction in porcine

Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.

Abstract A67: The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women

Abstract Background: In postmenopausal women, estrogen biosynthesis takes place predominantly in adipose tissue through the catalyzed conversion from androgens by the aromatase enzyme. Variation in the CYP19A1 gene, which encodes the aromatase enzyme, is involved in the regulation of estrogen levels. Recent evidence also suggests that estrogen regulates several cancer-related adipocytokines including hepatocyte growth factor (HGF). HGF acts as an angiogenic growth factor in both an autocrine and paracrine fashion in various cell types to promote cell migration, proliferation, and invasion. It is plausible that the CYP19A1 gene which alters estrogen production also influences HGF concentrations. We accordingly conducted an evaluation of the CYP19A1 gene in relation to circulating HGF levels among postmenopausal women in the Women's Health Initiative Observational Study (WHI-OS). Methods: We included in the present analysis a total of 45 CYP19A1 functional and common variants that were in Hardy-Weinberg equilibrium and had a minor allele frequency of ≥5%. As the distribution of HGF levels was highly skewed (p value for normality &amp;lt;0.001), we transformed HGF concentrations for all women into a log-, ranked-, or normal score (van der Waerden (VW) normal score method)-scale value. The associations between the CYP19A1 gene variants and the transformed HGF concentrations were assessed through a linear regression as implemented in PLINK with an additive scoring for 0, 1, or 2 copies of the minor allele of each variant. The analyzed models were adjusted for age (continuous) and body mass index (continuous). We also used linear regression to estimate haplotype-specific association with the rest of the haplotypes as the referents. To control for comparisons for multiple SNPs (or haplotypes), we performed 10,000 permutations to generate a gene-specific (familywise) empirical p value for each SNP (or haplotype) and to determine how frequently the identified association would occur by chance. We performed these permutations using the max(T) permutation option in PLINK. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and circulating HGF levels in ranked and normal score scales (corrected p values ≤0.04). Specifically, each additional copy of the minor allele of rs7172156 (T) and rs1008805 (C) was associated with lower mean HGF levels. By contrast, the minor alleles of rs6493494 (T), rs749292 (T), and rs11636639 (C) were each associated with higher HGF levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′ ≥97%, r2 ≥56%), collectively contributed ≥9% of total variance in ranked- and normal score-transformed HGF. Additionally, these 5 variants constituted block #6 of the CYP19A1 gene with 2 common haplotypes. One common haplotype (42%) containing the minor alleles of rs7172156 (T) and rs1008805 (C) was associated with lower HGF levels, whereas the other haplotype (40%) with the minor alleles of rs6493494 (T), rs749292 (T), and rs11636639 (C) was associated with higher HGF levels. The association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.17). Conclusion: Our study suggests a potential association between the CYP19A1 gene variants and circulating HGF levels in ranked or normal score scales. However, our findings are exploratory and require confirmation in larger observational studies. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A67.

Plasma Hepatocyte Growth Factor Elevation May Be Associated with Early Metastatic Disease in Primary Lung Cancer Patients

Hepatocyte growth factor (HGF), a ligand of the c-met proto-oncogene, exhibits activating effects on human lung cancer both in vitro and in vivo. However, few studies have reported the correlations between concentration changes of blood HGF and postsurgical prognosis. We evaluated whether surgery-related blood HGF elevation has prognostic significance in patients with surgically resected non-small cell lung cancer. We examined blood HGF concentration, c-met expression, and postoperative prognosis of 25 cases of primary resected, non-small cell lung cancer. We divided the patients into 2 groups according to receiver operating characteristics curve analysis using 7.2 ng/mL as the cut-off value of blood HGF concentration. Survival curve analysis revealed that patients with a high level of HGF (over the cutoff value) exhibited a poor prognosis of metastatic disease, compared to those in the low-level group after curative surgery (log rank test, P = 0.020; Wilcoxon test, P = 0.016). Elevation of HGF in plasma may be an important prognostic factor for early metastatic disease in patients with primary lung cancer. Moreover, inhibition of HGF elevation may have therapeutic effects on early distant metastasis of lung cancer.

Effects of different wave-length lights on proliferation and secretion of growth factors in human retinal pigment epithelium cells

Background The study of myopia development is always the hotspot worldwide. Recently,scientist found that some growth factor secreted by retinal nerve epithelium cells and retinal pigment epithelium(RPE)cells are associated with the development of myopia. Whenever, the absorption of RPE cells to different wave-length lights is different. ObjectiveThis study was to investigate the effects of different wave-lengths lights on the proliferation of human RPE cells, and explore the influence of different wave-lengths lights on RPE cells secreting hepatocyte growth factor(HGF) ,basic fibroblast growth factor(bFGF) and transforming growth factor-β(TGF-β).Methods The fourth to fifth passages of human embryonic RPE cells were exposed to blue light( λ =480 nm),red light( λ =775 nm) and white light. The cells of control group were harvested in normal condition. The proliferation and growth of RPE cells were assayed by MTT,and the ultrastructure of cells was examined under the transmission electron microscopy at 48 hours after light exposure of RPE cells. Enzyme linked immunosorbent assay(ELISA) was adopted to determine the concentrations of HGF,bFGF and TGF-β in the culture medium in 12,24,48,72 hours. The expression of HGF mRNA in RPE cells was detected by RT-PCR. This study was approved by Ethic committee of Fudan University. Results The A490 values of the cells exposed to blue light,red light,white light and white light were 0. 0218±0. 0014 ;0. 0353±0. 0025 ;0. 0371 ±0. 0024 and 0. 0445 +0. 0046 respectively with the significant difference among 4 groups ( F =12. 579, P＜0.05 ), and A490 value in blue light group, red light group were significantly lower than that of the control group ( t =2.043 ; t =2.024, P＜0.05 ). ELISA showed that the concentrations of HGF and TGF-β in culture medium were evidently elevated as the prolongation of light exposure in various light exposure groups in 72 hours(HGF) and 48 hours(TGF-β) compared with 12 hours with a predominating rise in the control group. The statistically significant differences were found in the concentrations of HGF and TGF-β between control group and blue light group or red light group in the( all P＜0. 05 ). The bFGF level was decreased with the time increase of various light exposure with the significant differences in 72 hours compared with 12 hours( P＜0.05 ). RT-PCR revealed the considerable difference about expression of HGF mRNA in RPE cells among these four groups( P＜0. 05 ), and the lest expression in HGF mRNA was in the blue light group compared with control group( t =3. 972,P＜0.05 ). Thinning of the chromatin, decreasing of organelle and loss of cellular membrane were seen in the blue light group, but no obvious change of ultrastructure of human embryo RPE cells was found in the ret and white light groups. Conclusions The irradiation of different wave-length light can effect the growth and proliferation and secretion of HGF,bFGF and TGFβ in human RPE cells in vitro,implying myopia formation is associated to exposure of different wave-length light. Key words: Myopia; Retinal pigment epithelial cell; Hepatocyte growth factor; Basic fibroblast growth factor; Transforming growth factor-β ; Light exposure

Soluble c-Met in serum of patients with multiple myeloma: correlation with clinical parameters

The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor (HGF), play key roles in tumour genesis and metastasis and contribute in multiple myeloma pathogenesis. Substantial data support that a soluble extracellular fragment of c-Met may function as a decoy receptor that downregulates the biological effects of HGF and c-Met. We examined serum levels of soluble c-Met in patients with myeloma and healthy individuals and investigated a possible relationship with clinical disease parameters and survival. The concentration of c-Met and HGF was measured by enzyme-linked immunosorbent assay in serum (n=49) and bone marrow plasma (n=16) from patients with multiple myeloma and in serum from healthy controls (n=26). The median serum concentration of soluble c-Met was 186 ng/mL (range 22-562) in patients with multiple myeloma and 189 ng/mL (range 124-397) in healthy individuals. There was a significant negative correlation between serum c-Met levels and disease stage, bone marrow plasma cell percentage and serum concentration of M-protein. We have for the first time examined the concentration of soluble c-Met in serum from patients with myeloma and found equal median levels in patients with myeloma as a group and healthy individuals. Still, serum levels of soluble c-Met correlated negatively with parameters of disease burden in patients with myeloma. We suggest that a possible role for the c-Met ectodomain as a negative regulator of HGF/c-Met activity should be examined in multiple myeloma.

Hepatocyte growth factor suppresses the anticancer effect of irinotecan by decreasing the level of active metabolite in HepG2 cells

In the liver, carboxylesterase (CES) converts irinotecan (CPT-11) to its active metabolite SN-38, which exerts anticancer effects. SN-38 is metabolized to an inactive metabolite SN-38 glucuronide by uridine 5′-diphospho-glucuronosyltransferase 1A1 (UGT1A1). Therefore, single nucleotide polymorphisms (SNPs) of the UGT1A1 gene are responsible for the severe adverse effects associated with the disruption of SN-38 metabolism. However, despite having SNPs of the UGT1A1 gene, many patients metabolize SN-38 sufficiently to avoid severe adverse effects. Among these patients, we found individuals with elevated serum concentrations of hepatocyte growth factor (HGF). The aim of this study was to evaluate whether HGF alters the metabolism of CPT-11, resulting in a reduction in the anticancer effect of CPT11. The cytotoxicity of CPT-11 and SN-38 was evaluated in HepG2 cells pretreated with HGF. Furthermore, we explored the level of expression and mechanisms of activity of CES and UGT1A1. HGF suppressed the cytotoxicity of CPT-11 by decreasing intracellular SN-38 levels that resulted from a decrease in CES2 and an increase in UGT1A1. Furthermore, this HGF-induced suppression was improved by pretreatment with an inhibitor of HGF receptor c-Met, and the improvement was synergistically potentiated by epidermal growth factor receptor (EGFR) inhibitors. Moreover, HGF induced phosphorylation of signal transducer and activator of transcription 3 and transactivated EGFR. These results suggest that HGF is a possible causative agent of acquired clinical resistance in chemotherapy with CPT-11 and could be useful as a predictor of clinical resistance. Additional treatment using c-Met and/or EGFR inhibitors could be a novel strategy to overcome resistance.

Characterization of Conditioned Media Collected from Aged versus Young Human Eye Cups

To characterize secretion of in situ retinal pigment epithelium (RPE) from healthy, aged adult, age-related macular degeneration (AMD) adult, and fetal donor eyes and to assess the impact on retinal survival in vitro. Conditioned medium (CM) was collected from adult and fetal donor eyes and analyzed for trophic factor composition by multiplex ELISA. Trophic factor receptor occupancy was calculated to evaluate differences in trophic factor concentrations. RPE trophic factor mRNA expression was quantified by real-time PCR. Retina-preserving activity of the collected CM was evaluated using degenerating porcine retina in vitro. Compared with CM from adult donors, AMD donor CM contained a significantly higher concentration of brain-derived neurotrophic factor (BDNF), whereas fetal donor CM contained significantly higher concentrations of hepatocyte growth factor (HGF) and pigment epithelium-derived factor (PEDF). No consistent correlation was found between trophic factor mRNA expression and protein secretion. Non-RPE components of the RPE-Bruch's membrane-choroid-sclera complex were major contributors of vascular endothelial growth factor-A (VEGF-A). CM of fetal donors was significantly better than CM of adult or AMD donors at improving the survival of degenerating porcine retina. RPE cells of adult and fetal eyes have significantly different trophic factor production capabilities, which correlated with changes in preservation of porcine retina. Combined with trophic factor receptor occupancy calculations, these data may implicate HGF and PEDF as key factors promoting the preservation of retinal structure and function.

Optimal concentration of hepatocyte growth factor for treatment of the aged rat vocal fold

Hepatocyte growth factor (HGF) demonstrates beneficial properties in the treatment of aged vocal folds. However, the optimal concentration of HGF remains unknown. The purpose of the present study was to investigate the effects of HGF concentration on treatment of the aged rat vocal fold. Prospective animal study. Seventy-five rats were studied. The rats were divided into five groups and received serial injections of HGF in 10 μL of phosphate-buffered saline (PBS) at the following concentrations: 10 ng/10 μL, 50 ng/10 μL, 100 ng/10 μL, 200 ng/10 μL, or control (PBS only). Alcian blue staining was performed to investigate hyaluronan (HA), and immunohistochemistry was performed to investigate collagen type I and III. Gene expression of hyaluronic acid synthase (HAS)-1, -2, matrix metalloproteinases (MMP)-2, -9, and procollagen I and III were also investigated using real-time polymerase chain reaction (RT-PCR). Histologic analyses revealed increased HA and decreased collagen type I in rats receiving injections of HGF at 100 ng/10 μL. Results were supported by RT-PCR revealing upregulated expression of HAS-2, decreased expression of procollagen I, and a significant increase of MMP-9 mRNA in rats receiving HGF at 100 ng/10 μL. We report the first in vivo concentration study of HGF for treatment of the aged vocal fold. Results revealed desirable biochemical effects of HGF at 100 ng/10 μL. These data will be used to provide immediate direction to programmatic efforts aimed at examining future applications of HGF for treatment of the aged vocal fold.

Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure

ObjectiveTo assess the prognostic value of the mitogenic, antiapoptotic, angiogenic and antifibrotic hepatocyte growth factor (HGF) in heart failure (HF).DesignProspective cohort study.Setting/patientsAssessment of HGF levels at inclusion in 351 patients...

Soluble CD30 and Hepatocyte growth factor as predictive markers of antibody-mediated rejection of the kidney allograft

Our retrospective study was aimed to assess the relevance of pre- and post-transplant measurements of serum concentrations of the soluble CD30 molecule (soluble CD30, sCD30) and the cytokine Hepatocyte growth factor (HGF) for prediction of the risk for development of antibody-mediated rejection (AMR) in kidney transplant patients. Evaluation of sCD30, HGF levels and the presence of HLA-specific antibodies in a cohort of 205 patients was performed before, 2 weeks and 6 months after transplantation. Patients were followed up for kidney graft function and survival for two years. We found a tendency of higher incidence of AMR in retransplanted patients with elevated pre-transplant sCD30 (≥ 100 U/ml) (p = 0.051), however no such correlation was observed in first-transplant patients. Kidney recipients with simultaneously high sCD30 and HLA-specific antibodies (sCD30+/Ab+) before transplantation had significantly lower AMR-free survival compared to the other patient groups (p < 0.001). HGF concentrations were not associated with the incidence of AMR at any time point of measurement, nevertheless, the combined analysis HGF and sCD30 showed increased incidence of AMR in recipients with elevated pretransplant sCD30 and low HGF levels. Conclusion: the predictive value of pretransplant sCD30 for the development of antibody-mediated rejection after transplantation is significantly potentiated by the co-presence of HLA specific antibodies. The role of HGF as a rejection-protective factor in patients with high pretransplant HGF levels would need further investigation.

The change and significance of Ki-67 expression following hepatocyte transplantation using hepatocyte growth factor loaded nanoparticles in rats with acute liver failure

Objective To evaluate the change and significance of Ki-67 antigen expression follow- ing hepatocyte transplantation using hepatocyte growth factor （HGF） loaded polylactic acid-O-carboxymeth-ylchitosan （PLA-O-CMC） nanoparticles in rats with acute liver failure （ALF）. Methods ALF models of rats were established by D-galactosamine intraperitoneal injection. Rat hepatocytes type Ⅰ collagen suspension （group Ⅰ ）, rat hepatocytes co-cultured with PLA-O-CMC nanoparticles （groups Ⅱ , Ⅳ ） and rat hepatocytes co-cultured with HGF loaded PLA-O-CMC nanoparticles （group Ⅲ ） （5 × 10^7 cells each group, 5 ml） were transplanted into the abdominal cavity of SD rats at 48 h after D-Gal injection. Intravenous injection of HGF （10μg/kg for 7 days） （group Ⅳ ） and RPMI 1640 injection （group V ） were used as the negative groups. The 14th-day survival rate of rats, pathological change and mitotic index of liver, Ki-67 antigen labeling index of ALF rat livers were observed. Results The 14th-day survival rate in groups Ⅰ -Ⅴ was 50. 00%, 68.75%, 81.25%, 75.00%, 18.75%, and that in nano-transplanted groups was higher than in group V. At the 3rd day, the concentration of HGF in liver tissue of group Ⅲ, average 5882.91 μg/L was the highest. The hepatic lobules structure in group Ⅲ recovered faster. The average mitotic index in group Ⅲ at the 5th day was 10. 20%0 and the average Ki-67 labeling index at the 7th day was 16. 8‰, which were all higher than in group V. Conclusion Intraperitoneal transplantation of HGF loaded PLA-O-CMC nanoparticle-attached hepatocytes for treatment of ALF can promote the liver regenerationassociated antigen expression. Key words: Hepatocyte transplantation; Acute liver failure ; Hepatocyte growth factor ; Nanoparticles ; Liver regeneration

HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic.

Urinary Excretion and Renal Production of Hepatocyte Growth Factor in Children with Henoch–Schönlein Purpura

This study measured urinary excretion and renal levels of hepatocyte growth factor (HGF) in children with Henoch-Schönlein purpura (HSP), examining the relationship between HGF, proteinuria and renal pathological changes. Seventy-eight patients with HSP aged 6 - 18 years were divided into three groups, based on urinary albumin excretion rate. Urinary HGF concentration was measured by enzyme-linked immunosorbent assay. Renal biopsies were performed in 22 patients; renal levels of HGF protein were determined immunohistochemically. Compared with controls, urinary HGF was significantly increased in patients with normoalbuminuria and microalbuminuria, especially in those with microalbuminuria; no differences were observed between patients with macroalbuminuria and controls. Little or no HGF was present in normal kidney, but HGF was present in renal tissue in all HSP patients, particularly those with microalbuminuria. Urinary HGF was strongly correlated with the presence of renal HGF. These results suggest that HGF is associated with proteinuria and renal pathological changes in children with HSP. The detection of urinary HGF in children with HSP may be a non-invasive, effective, method for early diagnosis of renal injury.

Circulating Stem Cell Populations in Preterm Infants

To investigate the association among different circulating stem cell (SC) populations, the levels of selected growth factors and chemokines regulating SC migration in the peripheral blood, and the incidence of retinopathy of prematurity (ROP). We evaluated 88 participants in this study: 29 preterm infants with ROP, 29 preterm infants without ROP, and 30 healthy full-term infants. Peripheral blood samples collected 10 weeks after delivery were analyzed using flow cytometry, immunofluorescence, real-time reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay. The following cell populations were analyzed: (1) lin⁻CXCR4(+)CD45⁻ (enriched in very small embryonic-like SCs), (2) lin⁻CXCR4(+)CD45(+) (enriched in hematopoietic SCs), and (3) CD34(+)CD133(+)CD144(+) (early endothelial progenitor cells) [lin indicates lineage]. The concentrations of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and stromal cell-derived factor 1 were measured in the plasma. The very small embryonic-like SCs and early endothelial progenitor cells expressing neural and endothelial markers were significantly increased in the preterm infants. The number of early endothelial progenitor cells in the peripheral blood was significantly greater in the preterm infants with ROP than in the preterm infants without ROP. An accompanying increase in the concentrations of vascular endothelial growth factor and hepatocyte growth factor was found in the peripheral blood of the preterm infants with ROP. No significant associations were found between hematopoietic SCs and ROP or prematurity. The increased number of early endothelial progenitor cells along with elevated levels of vascular endothelial growth factor and hepatocyte growth factor in preterm infants with ROP suggest that circulating vasculogenic factors may play a role in the development and progression of ROP. The increased number of very small embryonic-like SCs in preterm infants suggests that the development of immature tissues and organs, including the retina, may require a contribution of circulating SCs.

Impact of Serum Hepatocyte Growth Factor on Treatment Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non–Small Cell Lung Adenocarcinoma

The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKI treatment. We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, β-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor β polypeptide, placental growth factor, tenascin C, transforming growth factor-α, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated. The concentrations of HGF and VEGF were significantly higher among patients with progressive disease than among those without progressive disease (P < 0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P < 0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n = 20; wild-type, n = 23; unknown, n = 52) showed that higher HGF levels were significantly associated with a shorter PFS and OS (P < 0.0001 for both PFS and OS). These observations were also consistent in the subset analyses. Serum HGF was strongly related to the outcome of EGFR-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study.

Expression of hepatocyte growth factor in the serum and cerebrospinal fluid of patients with Parkinson’s disease

Hepatocyte growth factor (HGF), also known as scatter factor, promotes the survival and migration of immature neurons. The HGF receptor c-Met is expressed in neurons. HGF plays an important role as a neurotrophic factor in the brain. HGF is produced by a wide variety of cells and is found in many physiological fluids, including serum and cerebrospinal fluid (CSF). Since CSF is in contact with the extracellular space of the brain, biochemical brain modifications are, to some extent, reflected in the CSF, and peptide and growth factors in the CSF can be used as biomarkers of disease. In this study, CSF and serum HGF concentrations were measured in patients with Parkinson’s disease. The study population comprised 33 patients with Parkinson’s disease and 38 normal controls. Western blot analysis using an anti-HGF antibody confirmed the presence of HGF in serum and CSF. No significant changes in serum HGF were observed in this study. However, CSF HGF expression was higher in patients with Parkinson’s disease than in controls ( p < 0.001). This finding indicates that HGF may be involved in the pathophysiology of Parkinson’s disease.