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

Cell dispersion and motility are thought to be important steps in the invasion of tumor cells. The molecular mechanisms responsible for the induction of cell dispersion and motility remain unclear. Several factors affecting cell motility have been discovered. Among them, scatter factor (SF), a mesenchymal cell-derived protein, dissociates epithelial cell colonies into individual cells and stimulates the migration of epithelial cells. Purified SF promotes the invasiveness into collagen matrices of a number of human carcinoma cell lines, suggesting that SF is involved in the invasion of tumor cells. Recently, SF has been found to be identical to hepatocyte growth factor. Moreover, the c-met proto-oncogene product (the c-met protein) possessing a tyrosine kinase domain was identified as a receptor for SF. Three possible mechanisms have been postulated in which a tumor cell might increase its invasive potential through enhanced motility via SF and its receptor. First, in a cell already expressing the c-met protein, an unexpressed SF gene might be activated, leading to synthesis and secretion of the factor which could then initiate active motility in an autocrine fashion. Second, the tumor cell expressing the c-met protein may release a factor that affects surrounding mesenchymal cells, promotes synthesis and release of SF. The tumor cell would be stimulated in a paracrine fashion. Finally, the tumor cell may be exposed to SF already released by surrounding cells but may not be able to respond because it is partially or completely deficient in the c-met protein. Induction and increased expression of the c-met gene would result in the invasive phenotype of the tumor cell. Studies on these possible mechanisms will be required to elucidate the involvement of SF in the invasion of tumor cells.
 ...
PMID:[Scatter factor and cell motility]. 843 87

Gene changes in multiple oncogenes, multiple growth factors and multiple tumor-suppressor genes are observed in stomach cancer. Among them, those most commonly implicated in both well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma are inactivation (mutations and allele loss) of the p53 gene, and activation (abnormal expression and amplification) of the c-met gene. Moreover, they occur at an early stage of stomach carcinogenesis. In addition, loss of heterozygosity (LOH) on chromosome 5q (APC locus) is frequently associated with well-differentiated adenocarcinoma. LOH on chromosome 18q (DCC locus) and LOH of the bcl-2 gene also are common events of well-differentiated adenocarcinoma. LOH on chromosomes 1q and 7q may be involved in the progression of well-differentiated adenocarcinoma. Conversely, the development of poorly differentiated adenocarcinoma, in addition to changes in p53 and c-met genes, requires reduction or dysfunction of cadherin. Overexpression of bcl-2 protein is observed in poorly differentiated adenocarcinoma or signet-ring cell carcinoma. Moreover, the K-sam gene is amplified preferentially in poorly differentiated adenocarcinoma of scirrhous carcinoma. K-sam amplification in scirrhous carcinoma often occurs independently of c-met gene amplification. LOH on chromosome 1p also is relatively common in poorly differentiated adenocarcinoma. Exceptionally, signet-ring cell carcinoma shares APC mutations. There are some differences in expression of the growth-factor/receptor system between well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma. Moreover, interaction between cell-adhesion molecules in tumor cells expressing c-met and hepatocyte growth factor (HGF) from stromal cells is linked with morphogenesis of two histological types of stomach cancer. Intestinal metaplasia and adenoma of the stomach also contain p53 mutations and K-ras mutations or tpr-met rearrangement. Taken together, different genetic pathways of stomach carcinogenesis may exist for poorly differentiated and well-differentiated stomach cancers. Some of the latter may develop by a cumulative series of gene alterations similar to those of colorectal cancer.
 ...
PMID:Molecular mechanism of stomach carcinogenesis. 844 Jul 43

Hepatocyte growth factor/scatter factor (HGF/SF) is a stromally derived modulator of epithelial cell proliferation and morphology. To better assess the potential role of HGF/SF in tumor progression we sought to identify factors and biological conditions which regulate its expression. We show that several adult human primary fibroblast cultures from breast and prostate produce HGF/SF. HGF expression in the MRC-5 human fetal lung fibroblast cell line is stimulated by conditioned media harvested from human breast tumor cell lines (MCF-7, T47D, and MDA-MB-231). In contrast, both indirect and direct coculture of each of these tumor lines with MRC-5 fibroblasts down-regulates HGF/SF expression. Finally, we show that MRC-5 HGF expression is inhibited by several known peptide growth factors, including transforming growth factor beta, epidermal growth factor, and transforming growth factor alpha.
 ...
PMID:Regulation of fibroblast hepatocyte growth factor/scatter factor expression by human breast carcinoma cell lines and peptide growth factors. 844 2

Hepatocyte growth factor (HGF) was identified, purified and molecularly cloned as a potent mitogen for mature rat hepatocytes in primary culture. It is one of the largest cytokines and is composed of disulfide-linked subunits of approximately 60 (heavy chain) and 35 kilodaltons (light chain). Recent observations revealed that HGF is mitogenic to various epithelial cells other than hepatocytes and to endothelial cells, and that it also acts as a motogen, morphogen and tumor-suppressor as well as a mitogen. These various biological activities of HGF are presumably transduced through the same receptor, c-Met, which is a member of the tyrosine kinase receptor family. Although it shows multiple biological activities on cells in culture, HGF is most likely the physiological hepatotrophic factor which triggers liver regeneration. It may also function as a renotrophic and pulmotrophic factor after tissue injury. HGF production in the liver, kidney and lung increases after injury to these organs. An elevated HGF level may act as an inducer of compensatory DNA synthesis. The regulation of HGF production is, therefore, important for the control of organ regeneration. HGF is produced mainly by mesenchymal cells such as fibroblasts and vascular smooth muscle cells. Various types of human leukemia cells also secrete HGF both in vitro and in vivo. Some biological activities of HGF on hematopoietic cells, including co-mitogenic activity on myeloid leukemia cell lines, were recently demonstrated. HGF gene expression and the protein production in leukemia and fibroblast cells are modulated by various cytokines and hormones. Those modulators may indirectly affect organ regeneration and other biological processes by controlling HGF production.
 ...
PMID:Hepatocyte growth factor--pleiotropic cytokine produced by human leukemia cells. 853 10

Cell motility, a primary component of tumor cell invasion, is a continuum of sequential events in which the cell extends pseudopodia, forms nascent attachments, assembles and contracts the cytoskeleton, and finally, as it translocates forward, disengages distal adhesions. What triggers cells to move? Substratum contact mediated by integrin adhesion receptors is important, but other signals such as chemokinetic factors appear to be required for continued crawling. It is now apparent that integrins do not simply bind cells to matrix in a Velcro-like fashion, but also are potent signaling molecules. Initial engagement of integrins induces their condensation into focal contacts, forming anchors to the extracellular matrix and discrete signal-transducing complexes on the cytoplasmic surface. A number of growth factors, through either autocrine or paracrine pathways, can activate the cellular machinery that mobilizes the cell. Thus, these two classes of receptors--the integrin receptors that bind specific extracellular adhesion molecules, and growth factor receptors that bind their respective ligands--can regulate cell locomotion. Not surprisingly, there is 'cross-talk' between integrin and growth factor receptors that occurs through their common intracellular signaling pathways. In this way, each receptor type can either amplify or attenuate the other's signal and downstream response. An example of growth factor-induced motility is the epithelial-mesenchymal transition induced by hepatocyte growth factor/scatter factor (HGF/SF). When bound to its receptor, the c-met proto-oncogene product, HGF/SF induces a phenotypic conversion that appears to be an important aspect of tumor progression in malignant carcinomas. The motogenic response produced by HGF/SF in carcinoma cells occurs in discrete steps in which integrins and focal adhesion kinase (p125FAK) are first recruited to focal contacts. This is rapidly followed by cell spreading, disruption of focal adhesions and cell-cell contacts, and, finally, cell crawling. The precise mechanism by which growth factors such as HGF/SF and its receptor induce this motogenic response and modulate integrin function has not been clearly defined but appears to involve several signaling pathways. Understanding the process by which growth factor and integrin receptors interact and regulate motility may suggest novel targets for therapeutic intervention.
 ...
PMID:Growth factor regulation of integrin-mediated cell motility. 854 69

Kaposi's sarcoma is a highly vascularized multifocal tumor which frequently appears as a complication of HIV infection. It has been suggested that a disorder in the cytokine network may contribute to the development of the disease. We examined the expression of several cytokines in human sporadic Kaposi's-sarcoma specimens, as well as in spindle cells cultured from human lesions, and consistently found high levels of expression of hepatocyte growth factor (HGF). In addition, human lesion-derived spindle cells synthesize and secrete biologically active hepatocyte growth factor and express the hepatocyte-growth-factor receptor (c-MET). Moreover, elevated levels of transforming growth factor beta 1 (TGF beta 1) mRNA were found in lesions of human sporadic Kaposi's sarcoma and in lesion-derived spindle cells which also over-express urokinase. Since HGF, TGF beta 1 and urokinase are all involved in capillary-vessel organization, dysregulation of these interacting agents may play a role in the initiation and/or progression of Kaposi's sarcoma, stimulating the growth of spindle cells and recruiting endothelial cells into the lesion.
 ...
PMID:Over-expression of hepatocyte growth factor in human Kaposi's sarcoma. 856 12

Scatter factor (hepatocyte growth factor) is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through the c-met protooncogene product, a transmembrane tyrosine kinase that functions as the SF receptor. SF is a potent angiogenic molecule, and its angiogenic activity is mediated primarily through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF is chronically overexpressed in tumors, suggesting that it may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor-stroma interaction, in which the tumor cells secrete factors (SF-IFs) that stimulate SF production by tumor-associated stromal cells. Studies suggest a link between tumor suppressors (antioncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to the activation of an SF-IF-->SF-->c-met pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may, ultimately, provide clinically useful methods of enhancing or inhibiting angiogenesis.
 ...
PMID:Scatter factor and angiogenesis. 857 17

Hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF alpha) are potent mitogens for mature hepatocytes in primary culture (Nakamura, et al. 1984, Mead et al., 1989). However, these cytokines have completely different effects on tumor cell growth (Jhappan et al., 1990, Shiota et al, 1992). To clarify dual effects of these cytokines in liver, we developed double transgenic mice of HGF and TGF alpha using albumin promoter-HGF cDNA transgenic mice (AlbHGF) and metallothionein promoter-TGF alpha transgenic mice (MthTGF alpha). Double transgenic mice were examined on DNA synthesis, c-myc mRNA and occurrence of hepatocelular carcinoma (HCC). Higher labeling indices using BrDU were observed, in sequence, in AlbHGF mice, AlbHGF/MthTGF alpha, MthTGF alpha and wild type mice. Hepatic expression of c-myc mRNA in AlbHGF mice was elevated, compared to that in AlbHGF/MthTGF alpha or MthTGF alpha mice. After long-term observation, MthTGF alpha mice developed HCC in 6/10 (60%), whereas AlbHGF/MthTGF alpha mice developed HCC in 3/9 (33%). These data suggest that HGF is the potent mitogen, stimulating DNA synthesis and up-regulating c-myc mRNA. In addition, HGF may excert some inhibitory effect on occurrence of HCC by TGF alpha.
 ...
PMID:Characterization of double transgenic mice expressing hepatocye growth factor and transforming growth factor alpha. 858 43

It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth factors that contribute to liver regeneration occurring via both hepatocyte replication and oval cell proliferation. It is not clear, however, whether and to what extent these growth factors are also involved in hepatocarcinogenesis. In the present study, the gene expression of TGFalpha, HGF and aFGF and their corresponding receptors was examined by Northern blotting and in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber protocol. All three growth factor/receptor systems, TGFalpha/epidermal growth factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were significantly elevated at early time points when oval cells were proliferating. Their respective expression decreased after 1 month and remained at a low level until the development of liver tumors. In all hepatocellular carcinomas (HCC) examined, the transcripts of TGFalpha and aFGF were highly expressed, while those of HGF were low. With regard to the receptor expression in the tumors, EGFR was present at varying levels, c-met was expressed at higher levels and flg increased significantly, whereas bek remained at low levels. These data suggest that TGFalpha and aFGF are the major growth factors involved in the progression of HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC. Furthermore, HCC cells were phenotypically very similar to oval cells with regard to the gene expression of growth factor/receptor systems. These results, along with the finding that all the HCC cells are positive for the oval cell antigen OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells, strongly suggest that at least some of the HCC induced by the Solt-Farber protocol may be derived from oval cells.
 ...
PMID:Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis. 864 Sep 40

Liver is the most common distant metastatic site for colorectal cancers and when blood-borne colorectal cancer cells reach the liver, they first encounter hepatic capillary and sinusoidal endothelial cells. Thus we studied differences between highly (HT-29LMM) and poorly (HT-29P) liver-metastatic sublines of human colorectal cancer cells by examining the interactions between tumor cells and liver microvessel endothelial cells. Using hepatic sinusoidal endothelial (HSE) and lung microvessel endothelial (MLE) cell-conditioned medium we measured the growth and motility stimulating activities released from these endothelial cells and adhesion of these cancer cells to the endothelial cells. Differences in the ability of HSE-conditioned medium (HSE-CM) or MLE-conditioned medium (MLE-CM) to stimulate HT-29 cell growth were not observed. There was a small but significant increase in the rate of adhesion of highly metastatic HT-29LMM cells to HSE cell monolayers than poorly metastatic HT-29P cells, but there was no difference in adhesion to MLE cell monolayers. HSE-CM stimulated the motility of highly metastatic colorectal cancer cells to a greater extent than the poorly metastatic cells. Motility-stimulating activity for the colorectal cancer cell lines was not detected in MLE-CM. The HSE-CM motility-stimulating activity for human HT-29 cells was not removed using antibodies against hepatocyte growth factor (HGF/SF), complement component C3 or laminin, indicating that it is not related to these known liver-derived motility factors. The results suggest that the ability of highly metastatic HT-29LMM colorectal cancer cells to colonize the liver is related to their ability to respond to liver sinusoidal endothelial cell-derived motility factors and to a lesser degree to adhere to liver sinusoidal endothelial cells.
 ...
PMID:Differential motility stimulation but not growth stimulation or adhesion of metastatic human colorectal carcinoma cells by target organ-derived liver sinusoidal endothelial cells. 867 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>