Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor for Hepatocyte Growth Factor is a transmembrane tyrosine kinase encoded by the c-MET oncogene. We have previously shown that the Met protein is expressed in several human epithelial tissues. The receptor is barely detectable, however, in normal thyroids and in specimens from patients affected by non-neoplastic thyroid diseases. Now we report that the expression of the Met/HGF receptor is increased a hundred fold in 22 out of 41 human carcinomas derived from the thyroid follicular epithelium. A comprehensive analysis of 15 cases showed that the overexpressing carcinomas belong to histotype variants correlated with negative prognosis and in all but one case there were evidences of locally advanced disease and/or distant metastases. The 11 benign adenomas and the 5 medullary carcinomas tested were negative. Western blot analysis with monoclonal antibodies directed against either the intracellular or the extracellular receptor domains failed to reveal major structural alterations. Southern blot analysis also demonstrated that the c-MET gene was not amplified nor rearranged. These data suggest a role for the overexpression of c-MET oncogene in the pathogenesis and progression of thyroid tumors derived from the follicular epithelium.
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PMID:Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. 133 53

Previously, we demonstrated that hepatocyte growth factor/scatter factor (HGF/SF) is expressed by human bone stromal cells and is a powerful mitogen to prostatic epithelial cells in culture. Based on these observations, we hypothesized that, if prostate cancer cells in the prostate or bone environment respond to HGF/SF as a mitogen, then they must express the HGF/SF receptor, which is coded by the c-met proto-oncogene. We used immunohistochemical techniques to: 1) assess the presence and localization of c-met protein in benign and malignant human prostate tissues and 2) correlate the presence of c-met protein with tumor stage, grade and androgen sensitivity. c-met protein immunostaining was consistently observed in the basal epithelial layer of normal prostate glands but was absent in luminal epithelial cells of the peripheral and transition zones. c-met protein immunostaining was detected in 10 of 11 foci (91%) of high grade prostatic intraepithelial neoplasia (PIN). Overall, c-met protein staining was noted in 36 of 43 (84%) primary prostate cancer samples versus 2 of 11 (18%) benign prostate hyperplasia samples (p < 0.0001) and in 4 of 4 (100%) lymph node metastases, 23 of 23 (100%) bone marrow metastases and 1 of 3 (33%) other metastatic sites. There was a clear relationship between c-met protein staining and higher grade adenocarcinomas (p < 0.001). c-met protein is frequently detected in PIN and higher grade prostate cancers; future studies should evaluate the biological significance of these findings.
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PMID:c-met proto-oncogene expression in benign and malignant human prostate tissues. 753 65

Even though the liver is a relevant metastatic site for several human malignant tumors, mechanisms or organ-specific metastasis to the liver remain largely unknown. In the following paper we summarize the results obtained with different murine model systems which have been set up to elucidate the above mechanisms, and describe our own results with two murine models: the F9 teratocarcinoma and the B16 melanoma. While the F9 teratocarcinoma model system underscores the roles of both adhesion and growth stimulation in the target organ, the B16 melanoma model strengthens the relevance of paracrine growth stimulation. Moreover, B16 melanoma cells selected in vivo for increased liver colonization ability appear to depend on cell-to-cell contact with hepatocytes in order to gain efficient growth stimulation. When we next tried to identify the molecule(s) responsible for the growth effect in a liver plasma membrane extract, we found that such activity was mediated by two closely related protein bands. These turned out to be two different forms of transferrin (Tf), one of which is specifically present on the hepatocyte surface. Moreover, when we analyzed the different B16 lines for the expression of c-Met[the receptor for the hepatocyte growth factor-scatter factor (HGF/SF)], we found that liver-specific LS9 had more of this protein than lung-specific F10 or parental F1, suggesting a role for HGF/SF in liver colonization by B16 melanoma cells.
Invasion Metastasis
PMID:Murine models of liver metastasis. 765 28

The c-MET proto-oncogene encodes the receptor for the Hepatocyte Growth Factor/Scatter Factor, which is known to mediate mitogenic, motogenic and invasive responses of several cell types. We have analysed by immunohistochemistry and biochemically the expression of c-MET in benign and malignant melanocytic lesions. The Met/HGF receptor which in the melanocytic lineage displays the structural features of the authentic receptor was undetectable in tissue melanocytes and in nevocytic nevi. Only four out of 23 primary melanomas scored positive. Expression was increased to a significant level in 17 out of the 44 metastatic lesions examined. The c-MET expression was homogeneous in multiple metastases from the same patients. Comparative analyses showed both lack of correlation with the expression of the tumour progression associated ICAM-1 adhesion molecule and, in 23% of cases, co-expression with the c-KIT encoded receptor. These findings show that the c-MET gene is expressed at late stages of melanoma progression and suggest that the presence of Met/HGF receptor may contribute to the acquisition of an invasive phenotype.
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PMID:Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. 810 62

Hepatocyte growth factor (HGF), also known as scatter factor, regulates both cell motility and the growth of some cell types. We have determined the effects of HGF on the motility and growth of human colon cancer cell lines (HT115, HT29, HRT18 and HT55). Cell motility, as measured by dissociation from carrier beads or by scattering of cell colonies, was greatly increased in all cell lines. The effects were completely blocked by anti-HGF antibody. In contrast, cell growth of HT115, HT29 and HRT18 cells was inhibited by a wide range of concentrations of HGF. HT55 cell growth was also inhibited but needed a prolonged culture period (> 5 days). The HGF receptor/Met protein is highly expressed in the membrane fraction of these cells as determined by Western blotting. It is concluded that HGF has an effect on both colon cancer cell motility and growth, which may be important in the control of the spread of colon cancer.
Clin Exp Metastasis 1993 May
PMID:Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor. 838 69

The motility and invasion of cancer cells are basic requirements for the establishment of distant metastases. In this study, we examined the effect of invasion inhibiting factor 2 (IIF2), a motility/invasion regulatory agent, on the motility, invasion, growth and basement membrane attachment of human lung cancer cells. IIF2 significantly reduced cell dissociation, colony scattering and invasion induced by the motogenic factor, HGF/SF. Western and Northern analyses showed these cells to be positive for the HGF/SF receptor c-met. These effects were blocked by an anti-IIF2 antibody. IIF2 did not affect the growth and attachment of lung cancer cells to the basement membrane. It is concluded therefore that invasion inhibiting factor 2 is an inhibitor of human lung cancer cell motility and invasion in vitro and this may bear some importance in the construction of anti-metastatic therapies.
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PMID:Inhibition of motility and invasion of human lung cancer cells by invasion inhibiting factor 2. 885 42

An androgen-repressed human prostate cancer cell line, ARCaP, was established and characterized. This cell line was derived from the ascites fluid of a patient with advanced metastatic disease. In contrast to the behavior of androgen-dependent LNCaP and its androgen-independent C4-2 subline, androgen and estrogen suppress the growth of ARCaP cells in a dose-dependent manner in vivo and in vitro. ARCaP is tumorigenic and highly metastatic. It metastasizes to the lymph node, lung, pancreas, liver, kidney, and bone, and forms ascites fluid in athymic hosts. ARCaP cells express low levels of androgen receptor mRNA and prostate-specific antigen mRNA and protein. Immunohistochemical staining shows that ARCaP cells stain intensely for epidermal growth factor receptor, c-erb B2/neu, and c-erb B3. Staining is negative for chromogranin A and positive for bombesin, serotonin, neuron-specific enolase, and the c-met protooncogene (a hepatic growth factor/scatter factor receptor). ARCaP cells also secrete high levels of gelatinase A and B and some stromelysin, which suggests that this cell line may contain markers representing invasive adenocarcinoma with selective neuronendocrine phenotypes. Along with its repression of growth, androgen is also found to repress the expression of prostate-specific antigen in ARCaP cells as detected by a prostate-specific antigen promoter-beta-galactosidase reporter assay. Our results suggest that the androgen-repressed state may be central to prostate cancer progression and that advanced prostate cancer can progress from an androgen-independent to an androgen-repressed state.
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PMID:Androgen-repressed phenotype in human prostate cancer. 898 79

The c-MET oncogene encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), which is known to stimulate the invasive growth of epithelial cells cultured in vitro. The Met/HGF receptor is a heterodimeric transmembrane tyrosine kinase, which is a prototype for a new family of growth factor receptors. The c-MET oncogene is expressed in several types of epithelial tissue including keratinocytes and is over-expressed in a number of human carcinomas. Studies on various carcinoma cell lines have shown that over-expression and structural alteration of the receptor result in its activation and confer tumorigenesis. We have studied Met/HGF receptor expression in tissue specimens from 34 patients with head and neck squamous cell carcinomas (HNSCC) and in 17 regional lymph node metastases. Western blot analysis was employed, using monoclonal antibodies directed against either the intracellular or extracellular domain of the receptor. Each sample was compared to its normal counterpart. The receptor did not show any major structural alterations in HNSCC tissues, but its expression was increased from 2- to 50-fold in about 70% of tumors. Immunohistochemistry then showed that the same antibodies stained only a few cells in the basal layer of normal squamous epithelium but intensely marked tumor cells. In the lymph node metastases of Met-positive tumors, receptor expression was maintained and sometimes increased with respect to primary tumors. Immunohistochemical analysis of the metastatic lymph nodes showed that cells were negative in the normal lymphatic tissue and strongly stained in tumor cells. Over-expression of the Met/HGF receptor was found at all tumor stages but was more significant in those associated with enlarged or multiple (N2-N3) lymph node metastases. These data show that expression of the Met/HGF receptor may be involved in the progression of HNSCC towards a metastatic phenotype and may be a useful marker of head and neck tumor cell spread to regional lymph nodes.
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PMID:Detection of MET oncogene/hepatocyte growth factor receptor in lymph node metastases from head and neck squamous cell carcinomas. 906 49

Human gallbladder cancer is highly malignant and its prognosis is usually poor depending on the extent of surrounding tissue invasion. We examined in vitro the invasive activity of four gallbladder cancer cell lines (GB-d1, GB-h3, GB-d2 and FU-GBC-1) in the absence or presence of hepatocyte growth factor (HGF). In type 1 collagen gel culture, HGF stimulated cell proliferation and induced an invasive phenotype of arborizing structures in GB-d1, GB-h3 and GB-d2. In a Matrigel invasion assay, invasion was also induced in three of these cell lines by HGF but not in FU-GBC-1. Cellular motility was, however, stimulated by HGF in all of the four cell lines to various extents. Zymography for proteolytic enzymes demonstrated high levels of type IV collagenase and urokinase-type plasminogen activator (u-PA) activity in GB-d1, GB-h3 and GB-d2 even in the absence of HGF. In the presence of HGF, the 72 kDa type IV collagenase (MMP-2) activity of GB-h3 and u-PA activities of GB-d1, GB-h3 and GB-d2 were enhanced. In contrast, the MMPs and PAs activities of FU-GBC-1 were faint irrespective of the addition of HGF. A Western blot analysis demonstrated higher levels of 190 kDa c-MET product (HGF receptor) of GB-d1, GB-h3 and GB-d2 than that of FU-GBC-1. The invasion in the Matrigel assay stimulated by HGF was inhibited by protease inhibitors, aprotinin and FOY-305, as well as by anti-HGF antibody. These results thus suggest that, in addition to the importance of the proteolytic activity, the cellular motility induced via the HGF/HGF-receptor system is essential for the invasive progression of gallbladder carcinoma cells.
Clin Exp Metastasis 1998 Jan
PMID:Hepatocyte growth factor stimulates the invasion of gallbladder carcinoma cell lines in vitro. 950 79

We have analysed the role of hepatocyte growth factor/scatter factor (HGF/SF) in the process of morphogenesis and metastasis of epithelial (carcinoma) cells. HGF/SF induces various morphogenic responses in epithelial cells that derive from different tissues when these are grown in three-dimensional gels, e.g. branching tubules in kidney, breast, and prostate epithelial cells, crypt-like structures with brush border in colon epithelial cells, and alveolar-like aggregates in lung and pancreas cells. Epithelial cells are thus able to form complex structures in vitro which resemble the structures formed in the organ they originate from. We also examined the response of human breast carcinoma cells to HGF/SF in vivo. MDA MB 435 cells transfected with HGF/SF were injected into the mammary fat pad of nude mice, where they form tumours which spontaneously metastasize to the lungs. We found that expression of HGF/SF promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form complex structures in response to HGF/SF in vitro. These data demonstrate that the different responses to HGF/SF depend on the state of the epithelial cells: morphogenesis requires epithelial differentiation and cell polarity, whereas metastasis is observed when the cells have lost their epithelial characteristics. Moreover, we have recently identified Gab-1 as a direct-binding substrate of the c-Met receptor. Gab-1 binds to c-Met phosphorylated on tyrosine residues, but not to a number of other tyrosine kinases from different subfamilies. A newly identified proline-rich domain of Gab-1 is responsible for the binding to the bidentate docking site in c-Met. Expression of Gab-1 in epithelial cells is sufficient to induce c-Met-specific cellular responses which include the formation of branching tubules. Thus, Gab-1 seem to correspond to the substrate of the c-Met receptor tyrosine kinase that mediates the epithelial morphogenesis.
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PMID:Role of HGF/SF and c-Met in morphogenesis and metastasis of epithelial cells. 952 74


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