Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14210 (hepatocyte growth factor)
 6,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inappropriate expression of Met, the receptor for hepatocyte growth factor/scatter factor, has been implicated in sarcomagenesis via an autocrine mechanism. Sarcomas occur at high frequency in individuals with Li-Fraumeni syndrome as well as in p53-deficient mice. Here we show that these tumors express high levels of Met. Moreover, late passage fibroblast cell lines established from p53-deficient animals overexpress Met and can be tumorigenic in athymic nude mice, suggesting that progression occurs in vitro. The tumor explants display increased hepatocyte growth factor/scatter factor expression and Met turnover, indicating that autocrine Met activation contributes to tumor progression. Thus, the loss of wild-type p53 appears to greatly enhance the opportunity for inappropriate Met expression. Loss of p53 function does not by itself cause transformation, but inappropriate Met expression may be an important factor in sarcomagenesis.
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PMID:Met proto-oncogene product is overexpressed in tumors of p53-deficient mice and tumors of Li-Fraumeni patients. 772 66

In addition to its mitogenic, motogenic and morphogenic functions on various cell types, hepatocyte growth factor (HGF) also suppresses mitosis in several cancer cell lines, including carcinomas and sarcomas. Here we report that HGF is also mito-inhibitory in rat liver tumors induced by diethylnitrosamine. By using a double labeling technique employing [3H]thymidine and 5-bromo-2'-deoxyuridine to determine cell proliferation before and after HGF infusion, we determined that continuous infusion of 20 micrograms total HGF inhibited tumor cell proliferation by 50%. The labeling in non-tumor areas showed the reverse result in that the labeling was higher in HGF-treated rats than control rats. These results indicate that HGF has different effects on growth of normal and tumorous hepatocytes in vivo. These findings may be of relevance in understanding the role of HGF in hepatocarcinogenesis and provide added modalities for controlling growth of hepatocellular carcinomas.
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PMID:Hepatocyte growth factor inhibits cell proliferation in vivo of rat hepatocellular carcinomas induced by diethylnitrosamine. 772 65

Epithelia and mesenchyme interact during various physiologic and pathologic processes. Scatter factor is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. Recent studies suggest that scatter factor and its receptor (c-met) mediate mesenchyme/epithelia signalling and even interconversion. In this mini-review, we will discuss how scatter factor and c-met may mediate interactions between mesenchyme and epithelia during embryogenesis, organ repair, and neoplasia.
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PMID:Scatter factor and the c-met receptor: a paradigm for mesenchymal/epithelial interaction. 780 59

Stromal cells can dramatically affect the growth and metastatic capability of breast carcinoma cells. Growth factors, considered to be important mediators of this process, act as either mitogenic or mito-inhibitory regulators. We have developed an in vitro coculture system to examine the influence of adipocytes, a dominant mammary stromal cell type, on the growth of a murine mammary carcinoma, SP1. Previously, we have reported that conditioned medium (CM) from 3T3-L1 adipocytes can promote in vitro growth of SP1 cells. We now show that the major mitogenic signal derived from 3T3-L1 adipocyte CM is mediated by hepatocyte growth factor (HGF). Neutralizing antibody against HGF at 15 micrograms/ml completely abrogated mitogenic activity of 3T3-L1 CM. Furthermore, heparin, an inhibitor of biological activity of HGF, inhibited the mitogenic activity of 3T3-L1 CM. Western blot analysis also confirmed the presence of HGF in 3T3-L1 CM. Although basic fibroblast growth factor (bFGF) and insulin-like growth factor I (IGF-I) were mitogenic for SP1 cells, neutralizing antibodies against IGF-I, bFGF, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) did not inhibit the mitogenic activity of 3T3-L1 CM. Immunoprecipitation and immunoblotting of HGF receptor/c-met showed that c-met is expressed at high level in SP1 cells, and is phosphorylated following HGF ligation. Together, our present data demonstrate that 3T3-L1 adipocytes secrete HGF, which stimulates SP1 cell growth by a paracrine mechanism. Furthermore, the mitogenic effect of 3T3-L1 CM requires HGF receptor ligation and activation of tyrosine kinase signaling cascades in SP1 cells. These results highlight the importance of stromal-tumor cell interactions and suggest that HGF secreted by adipocytes may be a key regulator of mammary tumor growth.
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PMID:Role of hepatocyte growth factor in breast cancer: a novel mitogenic factor secreted by adipocytes. 781 85

The c-met protooncogene is a growth factor receptor with tyrosine kinase activity. Recently the hepatocyte growth factor was identified as the ligand for this receptor. Because the hepatocyte growth factor is a most potent mitogen in hepatocytes, possible involvement of c-met expression in hepatocarcinogenesis is suspected. In this study, we examined c-met expression in 23 hepatocellular carcinoma cases by means of Northern-blot analysis and an immunohistochemical study. Northern-blot analysis revealed c-met mRNA expression in the tumors of 6 of 19 patients (31.6%); in the immunohistochemical study, c-met protein was detected in 16 of 23 patients (69.6%). With both methods, c-met was found to be overexpressed in hepatocellular carcinoma compared with the surrounding normal liver. Comprehensive analysis showed that c-met protein expression was correlated with poor-to-moderate differentiation of cancer cells (p < 0.05). Tumor proliferative activity of hepatocellular carcinoma was evaluated by means of Ki-67 labeling index. All cases with increased tumor proliferative activity showed c-met protein expression, although the elevation of proliferative activity in the c-met-positive group was not statistically significant. These data suggest that the overexpression of c-met plays an important role in the development of hepatocellular carcinoma.
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PMID:Expression of the c-met protooncogene in human hepatocellular carcinoma. 792 56

Scatter factor (SF) (also known as hepatocyte growth factor [HGF]) is a fibroblast-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. SF may play major roles in development, repair, and carcinogenesis. However, the physiologic signals that regulate its production are not well delineated. We found that various human tumor cell lines that do not produce SF secrete factors that stimulate SF production by fibroblasts, suggesting a paracrine mechanism for regulation of SF production. Conditioned medium from these cell lines contained two distinct scatter factor-inducing factor SF-IF activities: a high molecular weight (> 30 kD), heat sensitive activity and a low molecular weight (< 30 kD) heat stable activity. Further studies revealed that SF-producing fibroblasts also secrete factors that stimulate their own SF production. We characterized the < 30-kD SF-IF activity from ras-3T3 (clone D4), a mouse cell line that overproduces both SF and SF-IF. The < 30-kD filtrate from ras-3T3 conditioned medium induced four- to sixfold increases in expression of SF biologic activity, immunoreactive protein, and mRNA by multiple SF-producing fibroblast lines. Ras-3T3 SF-IF activity was stable to boiling, extremes of pH, and reductive alkylation, but was destroyed by proteases. We purified ras-3T3 SF-IF about 10,000-fold from serum-free conditioned medium by a combination of ultrafiltration, cation exchange chromatography, and reverse phase chromatography. The purified protein exhibited electrophoretic mobility of about 12 kD (reduced) and 14 kD (nonreduced) by SDS-PAGE. The identity of the protein was verified by elution of biologic activity from gel slices. Purified SF-IF stimulated SF production in a physiologic concentration range (about 20-400 pM). Its properties and activities were distinct from those of IL-1 and TNF, two known inducers of SF production. We suggest that SF-IF is a physiologic regulator of SF production.
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PMID:Regulation of scatter factor production via a soluble inducing factor. 792 65

Alterations in multiple oncogenes and multiple tumor suppressor genes are observed in human gastro-intestinal cancer. Among them, the most frequently implicated in malignancy and metastasis of esophageal carcinoma may be amplification and overexpression of the human cyclin D gene. In gastric carcinoma, amplification and abnormal expression of the c-met gene encoding receptor for hepatocyte growth factor (HGF) may contribute to the tumor progression and metastasis. Interaction between cadherin in c-met overexpressed tumor cells and HGF from fibroblast may play an important role in morphogenesis of two histological types of stomach cancer. During stomach carcinogenesis the clone having critical p53 mutations may expand selectively to make up a finally advanced stage of malignancy and show metastasis. In colorectal cancer, loss of heterozygosity of the RB, p53 and DCC genes is frequently associated with liver metastasis. Overexpression of nm23 may participate in carcinogenesis and the reduction in nm23 expression is involved in metastasis in gastric and colorectal cancers.
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PMID:[Metastasis related genes and malignancy in human esophageal, gastric and colorectal cancers]. 809 50

Hepatocyte growth factor (HGF) is a stromally derived modulator of epithelial cell proliferation and motility. In the present study, we have measured immunoreactive (ir)-HGF concentration in tumor extracts of 258 primary human breast cancers using an enzyme-linked immunosorbent assay and have evaluated its association with disease-free and overall survival. The median value of ir-HGF concentration was 11.0 ng/100 mg protein (range, 1.4-566.7 ng/100 mg protein). Correlation analyses between ir-HGF concentration and clinicopathological factors showed that the ir-HGF level was correlated only with tumor size (P = 0.05). No significant associations were found between ir-HGF content and age, menopausal status, nodal status, histological type, histological grade, vessel involvement, estrogen receptor, progesterone receptor, type of surgery, or postoperative adjuvant therapy. Breast cancer patients with high ir-HGF concentration had a significantly shorter relapse-free (P = 0.001) and overall survival (P = 0.001) rate when compared to those with low ir-HGF concentration at the cutoff point of 21.7 ng/100 mg protein, which was determined in another group of 82 patients. In multivariate analysis, ir-HGF level was found to be the most important independent factor in predicting relapse-free and overall survival, of greater import than lymph node involvement. The putative role of HGF in breast cancer growth and metastasis is hereby strengthened.
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PMID:Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. 813 71

This study reports expression of mRNA for the growth modulator hepatocyte growth factor/scatter factor (HGF/SF) in both benign and malignant human mammary epithelium by in situ hybridization. In benign breast tissue expression was prominent in areas of adenosis and in peripheral acinic cells in lactating breast; in malignant epithelium expression was seen in 15 of 21 cases of in situ and invasive breast cancer. In some cases of invasive ductal carcinoma stronger labeling appeared to be associated with areas of tubule formation compared with areas of infiltrating growth, although this was not a universal finding. In contrast, two examples each of in situ comedo carcinoma and invasive lobular carcinoma were completely negative. HGF/SF mRNA extracted from a breast tumor demonstrated the expected 6-kb transcript on Northern blot analysis. These findings suggest the possibility of an autocrine loop for action of HGF/SF in proliferating mammary epithelium.
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PMID:Hepatocyte growth factor/scatter factor expression in human mammary epithelium. 816 Jul 69

Human hepatocyte growth factor has been purified from the plasma of patients with fulminant liver failure, but where this factor is produced in organs or cells of subjects with liver diseases is unknown. Therefore, we used a monoclonal antibody to human hepatocyte growth factor to stain cells in three normal and 29 diseased liver tissues by immunohistochemical techniques. By light microscopy, the immunostained cells seemed to be polymorphonuclear leukocytes because of their segmented nuclei. Some biliary epithelial cells also were stained. Electron microscopy confirmed that the immunostained cells with segmented nuclei were polymorphonuclear leukocytes and that the stained grains were on the membranes of rough endoplasmic reticulum, around specific or azurophilic granules and in the cell sap. Stained grains in the biliary epithelial cells were found sporadically on the inside and outside of the membranes of rough endoplasmic reticulum near the nuclei. Human hepatocyte growth factor is now known to be the same protein as scatter factor and tumor cytotoxic factor, both of which are produced by human fibroblasts in culture, but our results suggest that polymorphonuclear leukocytes in diseased livers are one cellular source of circulating human hepatocyte growth factor. The immunostaining properties of biliary epithelial cells in diseased livers also suggest that the cells produce and secrete human hepatocyte growth factor.
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PMID:Ultrastructural location of human hepatocyte growth factor in human liver. 817 37


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