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

Melanomas are highly variable with respect to aberrant gene expression and chromosomal lesions but share a common characteristic of an acquired independence from environmental growth factors that are needed for proliferation of normal melanocytes. Receptors with tyrosine kinase activity play a critical role in normal melanocyte proliferation and in the uncontrolled growth of melanomas. Normal human melanocytes depend on exogenous peptide growth factors such as basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or mast cell growth factor (MGF), all of which stimulate receptors with tyrosine kinase activity. In contrast, human melanoma cells from primary nodular and metastatic lesions grow autonomously partially because of inappropriate production of bFGF and continuous activation of the bFGF-receptor kinase. Animal models also provide evidence for the importance of receptor-tyrosine kinases in normal melanocyte proliferation and in malignant transformation. In the mouse, genes residing in three loci in which inactivation mutations lead to piebaldism, the dominant spotting (W), patch (Ph), and Sl encode, respectively, the receptor-kinases c-kit and platelet derived growth factor receptor, and the ligand for c-kit: MGF. In vivo transformation of mouse melanocytes to melanoma, due to constitutive expression of a transmembrane tyrosine kinase, the oncogene ret, was recently demonstrated in transgenic mice. Studies on a fish model, Xiphophorus, in which melanoma is inherited, showed that the dominant tumor inducing gene, Tu, encodes an EGF-receptor related tyrosine kinase which is expressed only in melanomas and not in normal tissues. Taken together, the results suggest that the uncontrolled growth of melanomas is due, in large part, to constitutive activation of receptors with tyrosine kinase activity.
Cancer Metastasis Rev 1991 Jun
PMID:Growth factors and tyrosine protein kinases in normal and malignant melanocytes. 187 53

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.
 ...
PMID:Biomarkers associated with prostate cancer progression. 752 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.
 ...
PMID:c-met proto-oncogene expression in benign and malignant human prostate tissues. 753 65

Tumour cell motility and attachment are crucial requirements in the formation of metastatic lesions. These properties are affected by a number of cytokines including hepatocyte growth factor/scatter factor (HGF/SF) and several immunoregulatory proteins, including interleukin-12 (IL-12). Although IL-12 has been reported to exhibit potent anti-tumour effects in vivo, a direct effect of IL-12 on cancer cells has not been reported. We show here that IL-12 directly inhibited the attachment of the human colon cancer cell lines HRT18, HT29 and HT115 to Matrigel, HGF/SF-stimulated cell motility and HGF/SF-induced cell invasion through a reconstituted basement membrane. IL-12 did not affect the growth of these cell lines. Flow cytometry, Western analysis and immunohistochemistry revealed an up-regulation of E-cadherin cell-surface adhesion molecules. These direct effects of IL-12 on colon cancer cells suggest a potentially important role for IL-12 in metastasis.
Clin Exp Metastasis 1995 Sep
PMID:Inhibition of cancer cell motility and invasion by interleukin-12. 764 24

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 met protooncogene product, Met, is the tyrosine kinase growth factor receptor for hepatocyte growth factor/scatter factor (HGF/SF). NIH 3T3 cells express HGF/SF endogenously and become tumorigenic in nude mice via an autocrine mechanism when murine Met is expressed ectopically (Metmu cells) or when human Met and human HGF/SF are coexpressed (HMH cells). Here, we show that Metmu and HMH cells are invasive in vitro and display enhanced protease activity necessary for the invasive phenotype. In experimental and spontaneous metastasis assays, Metmu or HMH cells metastasize to the lung, but lower numbers of subcutaneously injected Metmu and HMH cells produced invasive tumors in the heart, diaphragm, salivary gland, and retroperitoneum. It has been reported elsewhere that Met expression increased with tumor passage in athymic nude mice, and these tumor explants show enhanced activity in the metastasis assays. Autocrine-mediated Met-HGF/SF signal transduction in NIH 3T3 mesenchymal cells may provide an important system for understanding the biological process of metastasis.
 ...
PMID:Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. 819 26

Hepatocyte growth factor/scatter factor (HGF/SF) is a protein growth factor whose pleiotropic effects on epithelial cells include the stimulation of motility, mitosis and tubulogenesis. These responses are mediated by the cell surface tyrosine kinase receptor c-met. Because both the cytokine and receptor are found in the gastrointestinal tract, we have studied the effects of HGF/SF on transformed gut epithelial cells which express c-met. Here we describe the response of a new transformed human jejunal epithelioid cell line (HIE-7) to HGF/SF. Morphologically HIE-7 cells are immature. Their epithelial lineage was confirmed by reactivity with the epithelial specific antibodies AE1/AE3, Cam 5.2, Ber-EP4 and anti-EMA and is consistent with their expression of c-met mRNA and protein. In addition, electron microscopic analysis revealed the presence of primitive junctions and rudimentary microvilli, but features of polarization were absent. When grown on reconstituted basement membranes, HIE-7 cells formed closely associated multicellular cord-like structures adjacent to acellular spaces. However, the cells did not mature structurally, form lumen-like structures or express disaccharidase mRNA, even in the presence of recombinant HGF (rHGF). On the other hand, rHGF induced HIE-7 cells to scatter and stimulated their rapid migration in a modified wound assay. To determine whether the mitogenic effect caused by rHGF is associated with HIE-7 cell invasiveness across reconstituted basement membranes, a Boyden chamber chemoinvasion assay was performed. rHGF stimulated a 10-fold increase in the number of HIE-7 cells that crossed the basement membrane barrier, while only stimulating a small increase in chemotaxis across a collagen IV matrix, suggesting that the cytokine activates matrix penetration by these cells. rHGF also stimulated the invasion of basement membranes by an undifferentiated rat intestinal cell line (IEC-6) and by two human colon cancer cell lines which are poorly differentiated (DLD-1 and SW 948). In contrast, two moderately well differentiated colon cancer cell lines (Caco-2 and HT-29) did not manifest an invasive response when exposed to rHGF. These results suggest that HGF/SF may play a significant role in the invasive behavior of anaplastic and poorly differentiated gut epithelial tumors.
Clin Exp Metastasis 1994 Mar
PMID:Hepatocyte growth factor stimulates invasion across reconstituted basement membranes by a new human small intestinal cell line. 830 28

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

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.
Cancer Metastasis Rev 1995 Sep
PMID:Growth factor regulation of integrin-mediated cell motility. 854 69

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.
Clin Exp Metastasis 1996 May
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


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