High Levels Of Hepatocyte Growth Factor Research Articles

Identification of endophenotypes supporting outcome prediction in hemodialysis patients based on mechanistic markers of statin treatment

BackgroundStatins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level. MethodsWe generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA. ResultsThe impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year. ConclusionsIn this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.

Fibroblasts are the most suitable cell source for regenerative medicine due to their high intracellular fibroblast growth factor 2 content

In our previous study, we found that dry-preserved multilayered fibroblast cell sheets promoted angiogenesis and wound healing in a mouse ulcer model by releasing high levels of intracellular fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF), from dried cells. In the present study, to identify which cell types are suitable for human dry-preserved cell sheets (dry sheets), we compared the intracellular FGF2 levels in seven types of cells reported as cell sheets for clinical use or preclinical studies. FGF2 levels were high in mesenchymal cells, including human oral fibroblasts (HOFs) and human dermal fibroblasts (HDFs), human dental pulp stem cells (DPSCs), and human mesenchymal stem cells (MSCs); in contrast, FGF2 levels in human umbilical vascular endothelial cells (HUVECs), human skeletal muscle myoblasts (SkMMs), and human epidermal keratinocytes (HEKs) were remarkably low, approximately 25% those in fibroblasts. In addition, we prepared dry sheets from HOFs, DPSCs, and MSCs, and analyzed the growth factors released from each dry sheet upon rehydration. High levels of FGF2, HGF, and VEGF were detected in the eluate prepared by immersing each dry sheet. In particular, FGF2 and HGF were the most abundant in HOFs. An in vitro cell proliferation assay showed that these eluates significantly enhanced HUVEC proliferation compared to control cells. Furthermore, cells incubated with HOF eluate showed significantly higher cell proliferation than cells incubated with DPSC and MSC eluates. However, this proliferative response was significantly blocked by FGF2-neutralizing antibodies. These results demonstrate that growth factors released from human dry sheets have physiological activity and that this activity is mainly mediated by the effect of FGF2. Fibroblasts are ideal for the clinical application of dry-preserved cell sheets in humans owing to their high intracellular FGF2 content, fast cell proliferation, ease of handling, availability, and low culture costs, making them the most suitable cell source for regenerative medicine, with FGF2 release as the mechanism of action.

Final efficacy and safety results and biomarker analysis of a phase 2 study of cabozantinib in Japanese patients with advanced renal cell carcinoma

BackgroundCabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment.MethodsJapanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses.ResultsIn total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1–131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1–40.6). Kaplan–Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4–18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6–85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline.ConclusionsUpdated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219.

Hepatocyte growth factor combined with adenosine deaminase as biomarker for diagnosis of tuberculous pleural effusion.

The simple, rapid, and accurate diagnosis of tuberculous pleural effusion (TPE) remains difficult. This study aimed to determine the accuracy of hepatocyte growth factor (HGF) in the diagnosis of TPE. We quantified the expression of HGF, adenosine deaminase (ADA), and interferon gamma (IFN-γ) in pleural effusion (PE) in 97 TPE subjects and 116 non-TPE subjects using an enzyme-linked immunosorbent assay (ELISA) or a fully automatic biochemical analyzer. The diagnostic performance of these three biomarkers was evaluated using a receiver operating characteristic (ROC) curve of subjects by age and gender. We discovered that the TPE group had much higher levels of HGF than the non-TPE group, regardless of age or gender, and that there was no statistically significant difference between the two groups' levels of HGF expression in peripheral plasma. In female TPE patients aged ≤65 years, the AUCs of TPE and non-TPE diagnosed by HGF, ADA or IFN-γ were 0.988, 0.964, and 0.827, respectively. HGF plus ADA had the highest diagnostic efficacy in female TPE patients aged ≤65 years. With HGF plus ADA having a cut-off value of 0.219 for distinguishing TPE from non-TPE, the area under the curve (AUC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) were, respectively, 0.998 (95% confidence interval [CI], 0.993-1.000), 100 (95% CI, 89.997-100.000), 96.667 (95% CI, 82.783-99.916), 97.222 (95% CI, 83.594-99.586), and 100. This study confirmed that HGF plus ADA has high diagnostic efficacy in younger female TPE patients and has the potential to be an excellent biomarker.

Abstract 5138: Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer

Abstract Background: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the therapeutic implications of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancer (CRC). Methods: Clinical outcomes were analyzed according to the plasma HGF levels in patients with metastatic CRC (mCRC) receiving palliative first-line cetuximab or bevacizumab + FOLFIRI chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition in the HGF-high population. Results: From March 2015 to September 2019, a total of 80 patients were enrolled. The median age was 63 (range, 24-85) years. Of these, 45 patients (56.2%) were treated with bevacizumab + FOLFIRI and 35 patients (43.8%) were treated with cetuximab + FOLFIRI. Among patients with evaluable disease (43 patients (95.6%) in the bevacizumab group and 34 patients (97.1%) in the cetuximab group), the objective response rate was 60.0% and 37.8%, respectively (p=0.162). The median serum HGF level was 374.75 (range, 9.43-30,644.44) pg/mL, and the optimal cut-off value of HGF levels was 12.70 pg/mL by the maximal chi-square method. During a median follow-up of 29.3 (range, 1.2-71.3) months, both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the high HGF group compared with the low HGF group: median 11.8 (95% confidence interval [CI], 10.5-13.1) months vs. 24.7 (95% CI, 23.4-25.9) months for PFS (p=0.009), and median 21.1 (95% CI, 17.9-24.3) months vs. not reached for OS (p=0.018). The difference in PFS and OS was statistically significant in the cetuximab group (p=0.003 for PFS and p=0.035 for OS), but not in the bevacizumab group. In five RAS/RAF wild-type CRC cell lines (Caco-2, COLO 320DM, KM12C, SNU-C1, and SNU-C4), the addition of HGF activated ERK1/2 and AKT via MET phosphorylation. In the cytotoxicity assays, Caco-2 and SNU-C4 were relatively sensitive to cetuximab compared with the others and, in the presence of HGF, cetuximab sensitivity was significantly decreased in the two cells. Moreover, capmatinib, a MET inhibitor, abrogated the effect of HGF on common downstream signaling pathways of EGFR and MET and thus the cetuximab resistance was significantly overcome in vitro. Conclusions: Among patients with mCRC receiving cetuximab + FOLFIRI, those with high plasma HGF levels had significantly worse PFS and OS. HGF induced cetuximab resistance by AKT and ERK activation while capmatinib, a MET inhibitor, significantly increased the anti-tumor effects of cetuximab in the presence of HGF in vitro. Our data may provide evidence of future clinical trials of dual EGFR and MET targeting strategies in patients with HGF-high, RAS/RAF wild-type mCRC. Citation Format: Sang-A Kim, Hyejoo Park, Kui-Jin Kim, Ji-Won Kim, Ji Hea Sung, Milang Nam, Ju Hyun Lee, Eun Hee Jung, Koung Jin Suh, Ji Yun Lee, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee, Keun-Wook Lee. Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5138.

Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites, leading to an extremely poor prognosis. We had demonstrated that paracrine hepatocyte growth factor (HGF)-induced MET activation promotes peritoneal carcinomatosis with ascites formation. The vascular endothelial growth factor (VEGF) receptor (VEGFR)/VEGF axis facilitates tumor progression and formation of malignant ascites. This study investigated the role of MET and VEGFR2 in the development of peritoneal carcinomatosis with malignant ascites. Cabozantinib is a dual inhibitor of MET and VEGFR2. We examined the effects of cabozantinib on MET- and VEGFR2-mediated progression of peritoneal carcinomatosis in human scirrhous gastric cancer in vitro and in vivo. Cabozantinib inhibited HGF-stimulated proliferation of scirrhous cancer cell lines NUGC4 and GCIY, with a high potential to generate peritoneal carcinomatosis with ascites fluid, as well as the constitutive proliferation of MKN45 cells with MET amplification. Cabozantinib also inhibited the phosphorylation of both MET and VEGFR2 in scirrhous cancer cells and HGF- or VEGF-stimulated HUVECs. It effectively reduced ascitic fluid and prolonged the survival of NUGC4-inoculated nude mice. In clinical specimens, malignant ascites fluid from patients with peritoneal carcinomatosis contained high levels of HGF and VEGF. Our results strongly suggest that MET- and VEGFR2-mediated signaling pathways play pivotal roles in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, the dual blockade of MET and VEGFR2 signaling may be a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer.

Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.

Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7months, respectively, for PFS (p = 0.009), and median 21.1months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Abstract 13300: Hepatocyte Growth Factor and 10-year Change in Left Ventricular Structure: The Multi-Ethnic Study of Atherosclerosis

Introduction: Hepatocyte Growth Factor (HGF) is a mesenchymal cytokine linked to incident heart failure (HF), with recent data from our group showing a strong and independent association with HF with preserved ejection fraction (HFpEF). Cardiac MRI (cMRI) allows for precise analysis of morphologic changes in left ventricular (LV) structure. Increasing LV mass and concentric remodeling (defined by an increasing mass:volume ratio) are imaging markers of HFpEF risk. Whether HGF is associated with adverse LV remodeling over time is unknown. Hypothesis: Higher HGF will be associated with increasing LV mass, decreasing LV volume and increasing mass:volume ratio over 10 yrs. Methods: We studied 4762 participants of the MESA cohort, free of cardiovascular disease (CVD) and HF at baseline, who completed both HGF measurement and cMRI at baseline. Participants with LV EF<50% were excluded. Of these, 2855 completed a 2 nd cMRI at 10 yrs. We examined the cross-sectional and longitudinal associations of HGF and LV parameters using multivariable-adjusted linear mixed effect models. Results: The mean (SD) for age was 61 (10) yrs. Median (IQR) for HGF level was 888 pg/mL (745-1066); 53% women. At baseline, the 3 rd HGF tertile, compared to the 1 st , was associated with greater mass:volume ratio [relative difference 1.66 (0.43, 2.89)] and lower LV end diastolic volume [-1.87 mL (-3.45, -0.28)], after adjustment for CVD risk factors and NT- proBNP (model 2) [Table] . In longitudinal analysis, the 3 rd HGF tertile was also associated with increasing mass:volume ratio [difference in 10-yr change: 4.79 (2.73, 6.85)] and decreasing LV end diastolic volume [-4.97 (-7.10, -2.85)]. Conclusions: In a community cohort, higher HGF levels were independently associated with a concentric LV remodeling pattern of increasing mass:volume ratio and decreasing LV end diastolic volume over 10 yrs. This association may suggest an intermediate phenotype explaining the association of HGF with HFpEF risk.

Adipose-Derived Stem Cells Promote Proliferation and Invasion in Cervical Cancer by Targeting the HGF/c-MET Pathway.

BackgroundCervical cancer is a serious female malignancy affecting women’s health worldwide. The HGF/c-MET signaling pathway is activated in cervical cancer. Adipose-derived stem cells (ADSCs) with multipotential differentiation can carry out paracrine secretion of hepatocyte growth factor (HGF). Here, we investigated the effect and underlying mechanism of ADSCs on the promotion and invasion of cervical cancer in vitro and in vivo.Materials and MethodsADSCs were isolated, identified, and co-cultured with cervical cancer cells. HGF was detected using ELISA, and the HGF and c-MET signaling pathway was assessed with Western blot. The proliferation and invasion of human cervical cancer cell lines (HeLa and CaSki cells) were measured using CCK-8 and transwell assays. A HeLa xenograft mouse model was established to determine the effect of ADSCs on tumor growth in vivo.ResultsADSCs secreted a high level of HGF into the supernatant, while co-culture of ADSCs and cervical cancer cells increased the supernatant level of HGF. The HGF/c-MET pathway was activated in HeLa and CaSki cells co-cultured with ADSCs. Both co-culture with ADSCs and use of ADSC-derived conditioned medium (ADSCs-CM) significantly promoted the proliferation and invasion of cervical cancer cells in vitro, an effect that was reduced by inhibiting tumor cell c-MET expression. Furthermore, ADSCs-CM promoted HeLa cervical tumor growth in vivo, which could be suppressed by intratumoral c-MET siRNA injection.ConclusionADSCs promote cervical cancer growth and invasion through paracrine secretion of HGF and involvement of the HGF/c-MET signaling pathway.

The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor κB (NF-κB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-κB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-κB signaling pathway, and Met and NF-κB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-κB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.

A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway.

Background: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.

Association of Circulating Hepatocyte Growth Factor and Risk of Incident Peripheral Artery Disease: The Multi-Ethnic Study of Atherosclerosis.

Higher levels of hepatocyte growth factor (HGF) have been associated with the presence of peripheral arterial disease (PAD), but prospective associations are unknown. We examined the association of circulating HGF levels with incident PAD. Between 2000 and 2002, HGF was measured in 6742 Multi-Ethnic Study of Atherosclerosis participants without PAD. Incident clinical PAD, adjudicated on the basis of a positive history for the presence of disease-related symptoms or treatment, was ascertained through 2015. Incident low ankle-brachial index (ABI), defined as an ABI < 0.9 and a decline of ≥ 0.15, was assessed among 5736 individuals who had an ABI > 0.9 at baseline and ≥1 follow-up ABI measurement 3 to 10 years later. There were 116 clinical PAD and 197 low ABI events that occurred over a median follow-up of 14 and 9 years, respectively. After adjustment for demographic and clinical variables, a standard deviation increment of HGF (303 ng/L) was associated with an increased risk of clinical PAD (hazard ratio: 1.21; 95% confidence interval [CI]: 1.05-1.39) but not a low ABI (rate ratio: 1.03; 95% CI: 0.85-1.25). In conclusion, higher HGF levels were modestly associated with an increased risk of developing clinical PAD.

Hepatocyte growth factor levels in livers and serum at Kasai-portoenterostomy are not predictive of clinical outcome in infants with biliary atresia

Biliary atresia (BA) is characterized by progressive destruction of the biliary system leading to liver fibrosis and deterioration of liver function. Serum hepatocyte growth factor (HGF) has been shown to be increased in cirrhotic diseases including BA. The aim of this study was to investigate the prognostic value of HGF levels in sera and liver tissue for the further disease course. A total of 49 serum and liver samples from infants with BA were acquired during Kasai-portoenterostomy (KPE) and analyzed by multiplex immunoassay including HGF, as marker of liver regeneration, and Interleukin 6 (IL-6) as a marker of inflammation. Both mediators showed no correlation with the outcome defined as favorable (survival with native liver (SNL)) or, in contrast, rapid deterioration of liver function requiring transplantation. Our data suggest that the degree of liver regeneration indicated by high levels of HGF within the liver is a dismissible factor in the post-KPE disease course.

Mechanisms of the Immunomodulation Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Facial Nerve Injury in Sprague-Dawley Rats.

Normal facial nerve (FN) function is very important for human being. However, if injured, FN function is difficult to restore completely. Recently, many studies reported the immune regulation function of stem cells (SCs). However, the immunomodulation function of SCs on FN injury is still unclear. Our study aims to explore the mechanism of immunomodulation effect of Sprague-Dawley rat bone marrow-derived SCs (BMSCs) on FN injury and specially focus on the regulation of Th17 and the protection effects of BMSCs on central facial motor neurons (FMNs). First, rat FNs were harvested. FN and BMSCs were cultured together or separately and levels of transforming growth factor (TGF)-β1, interleukin (IL)-6, hepatocyte growth factor (HGF), inducible nitric oxide synthase (iNOS), and prostaglandin E2 (PGE2) in supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Then, after treating with or without local BMSCs injection, the proportion of Th17 in neck lymph nodes (LNs) was investigated in rat FN injury models. Furthermore, the apoptotic index of FMNs was studied in rat FN injury models that were treated with or without BMSCs. We found that BMSCs could secrete high levels of IL-6, HGF, PGE2, iNOS, and TGF-β1 in culture. The percentage of Th17 of neck LNs in BMSCs-treated group was significantly lower than that in the control group. The apoptotic index of FMNs in BMSCs-treated group was significantly lower than that in the control group. In conclusion, our research indicates BMSCs could independently secrete cytokines IL-6, HGF, PGE2, iNOS, and TGF-β1, and these cytokines could regulate the balance among subsets of CD4+ T cells and could protect FMNs by inhibiting neuron apoptosis.

Effect of serum HGF and CK18 in patients with laryngeal cancer on postoperative prognosis

Objective: To investigate the correlation between the levels of serum cytokeratin 18 (CK18) and hepatocyte growth factor (HGF) and tumor stage and prognosis in patients with laryngeal carcinoma. Method: Patients with laryngeal cancer who were admitted to our hospital from January 2012 to December 2013 were enrolled. Blood samples were collected for CK18 and HGF detection, and postoperative prognosis data were collected at regular follow-up. Result: The serum CK18 and HGF concentration of patients with poorly differentiated tumor, high tumor grade and clinical stage were significantly higher than those with well differentiated tumor, low tumor grade and low clinical stage (P<0.05). The 5-year survival rate (69.9%) of patients with laryngeal cancer in the high CK18 group was significantly lower than that in the low CK18 group (92.3%) (P<0.05), and the 5-year survival rate (71.1%) of patients with laryngeal cancer in the high HGF group was significantly lower than that in the low HGF group (94.2%) (P<0.05). The results of univariate analysis showed that tumor type, differentiation, T grade, N grade and clinical stage affected the survival rate of patients with laryngeal cancer. Cox regression model analysis showed high CK18 and high HGF levels were risk factors for poor prognosis ［CK18 HR: 2.594 (1.558-4.318); P<0.001, HGF HR: 2.671 (1.605-4.446); P<0.001］. Conclusion:The results suggested that serum CK18 and HGF levels can be used as prognostic and disease monitoring biomarkers for laryngeal cancer.

Disproportionately high levels of HGF induce the degradation of the c-met receptor through the proteasomal degradation pathway

Hepatocyte growth factor (HGF) receptor is a member of the receptor tyrosine kinases (RTKs) and has been reported to perform diverse functions in various cell types during both the developmental and adult stages. Among different roles, HGF is best known for its angiogenic effects of inducing the migration of endothelial cells. Because angiogenesis is one of the prerequisite steps for tumor metastasis, HGF-dependent cell migration has to be tightly controlled. However, the underlying mechanisms regulating the optimum level of HGF/c-met signaling have been poorly understood. In this study, we tested whether the migration of endothelial cells is regulated by a negative feedback mechanism under disproportionately large amounts of HGF. Data from endothelial cell migration assays showed that HGF activity increased as its concentration increased, but declined beyond a certain point. Under limiting conditions, amounts of phosphorylated Erk and Akt surged, reaching a plateau in which the enhanced level was more or less maintained. The c-met receptor was degraded when unnecessarily large amounts of HGF were present. Under these conditions, HGF could no longer activate downstream signaling pathways even if cells were re-treated with optimal amounts of HGF. Excessive doses of HGF increased the phosphorylation of tyrosine residue 1003 involved in the ubiquitination of c-met, and phosphorylated c-met was diverted toward the proteasomal degradation pathway. Taken together, HGF/c-met signaling is tightly regulated by a negative feedback loop through an ubiquitin-proteasomal degradation pathway.

Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer's Dementia.

Background: While hepatocyte growth factor (HGF) is known to exert cell growth, migration and morphogenic effects in various organs, recent studies suggest that HGF may also play a role in synaptic maintenance and cerebrovascular integrity. Although increased levels of HGF have been reported in brain and cerebrospinal fluid (CSF) samples of patients with Alzheimer’s disease (AD), it is unclear whether peripheral HGF may be associated with cerebrovascular disease (CeVD) and dementia. In this study, we examined the association of baseline serum HGF with neuroimaging markers of CeVD in a cohort of pre-dementia (cognitive impaired no dementia, CIND) and AD patients.Methods: Serum samples from aged, Non-cognitively impaired (NCI) controls, CIND and AD subjects were measured for HGF levels. CeVD (cortical infarcts, microinfarcts, lacunes, white matter hyperintensities (WMH) and microbleeds) were assessed by magnetic resonance imaging (MRI).Results: After controlling for covariates, higher levels of HGF were associated with both CIND and AD. Among the different CeVD MRI markers in CIND and AD, only small vessel disease, but not large vessel disease markers were associated with higher HGF levels.Conclusion: Serum HGF may be a useful peripheral biomarker for small vessel disease in subjects with cognitive impairment and AD.

Prevalence of Hepatocyte Growth Factor and Autoantibodies to α-HGF as a New Etiology for Bilateral Diffuse Uveal Melanocytic Proliferation Masquerading as Neovascular Age-Related Macular Degeneration.

Objective:The goal was to test the hypothesis that high serum hepatocyte growth factor (HGF) and retinal autoantibodies against α-HGF contribute to the pathology of bilateral diffuse melanocytic proliferation (BDUMP).Methods:Case report of an elderly diagnosed with neovascular age-related macular degeneration (n-AMD) treated with bilateral Bevacizumab injections. Examination included comprehensive ophthalmic examination and images obtained by fundus photography, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography (OCT), and B-scan ultrasonography. The levels of HGF and circulating HGF receptor (c-MET) were measured in the serum by ELISA and anti-retinal autoantibodies by western blotting.Results:Patient received Bevacizumab injections for presumed n-AMD and had a history of papillary renal cell carcinoma stage 4 with a tumor containing gene mutation Y1230C in the mesenchymal-epithelial transition factor (MET). Visual acuity was 20/200 OD and CF OS. Multimodal imaging was consistent with BDUMP. Plasma exchange therapy was recommended but could not be started until 10 months later due to deterioration in his medical condition. Pre- and post-plasma exchange sera demonstrated anti-retinal autoantibodies against 69-kDa protein of the same molecular weight as the α-HGF. Serum autoantibodies reacted with purified recombinant α-HGF on the blot.Conclusions:BDUMP can mimic n-AMD, which can delay treatment. Plasma exchange resulted in resolved inflammation, resolution of exudative detachments and improved vision after cataract surgery. Consideration of the tumor genetics led to the recognition of elevated HGF levels and autoantibodies to α-HGF (anti-69-kDa), which suggested a new pathogenic mechanism of BDUMP. We believe that therapy with tyrosine kinase inhibitors and a checkpoint inhibitor may contribute to the high HGF levels and subsequent immune response.

Differential expression of hepatocyte growth factor in patients with systemic sclerosis-associated pulmonary arterial hypertension

Introduction Non-invasive biomarkers are needed to identify pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients who may benefit from early intervention. We sought to identify novel cytokines that differentiate patients with incident SSc-PAH from those at high risk for PAH. Methods The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry is a multicenter registry of SSc patients at high risk for PAH (at-risk) or with incident right-heart catheterization-confirmed PAH (definite PAH). Serum from 10 at-risk and 9 definite PAH patients were profiled with Bio-PlexTM bead arrays for 48 cytokines and chemokines. We also evaluated the longitudinal change in cytokine profiles from 3 at-risk patients who subsequently developed definite PAH. Results Clinical features of at-risk versus definite PAH patients were not significantly different except for right-ventricular systolic pressure on echocardiogram (34 ± 7 vs. 45 ± 8 mmHg, p = 0.006), left atrial diameter (2.9 ± 0.5 vs. 3.7 ± 0.4 cm, p = 0.02), 6-minute walk distance (508 ± 115 vs. 393 ± 70 m, p = 0.02), mean pulmonary artery pressure (18 ± 4 vs. 32 ± 6 mmHg, p = 0.01), and pulmonary vascular resistance (111 ± 48 vs. 272 ± 109 dyn/s/cm5, p = 0.009). Serum cytokine profiling identified hepatocyte growth factor (HGF) as the only cytokine significantly different between the at-risk and definite PAH groups (225.8 ± 55.0 vs. 361.6 ± 164.5 pg/mL, q&lt;0.1%). Profiling of longitudinal samples of at-risk to definite PAH patients did not identify any significant changes in HGF or other cytokines over time. Conclusions Definite PAH patients expressed higher levels of HGF than at-risk patients. Further studies are needed to clarify the utility of HGF as a predictive biomarker for SSc-PAH.

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome.The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients.We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124).High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.