Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteopontin (OPN) is a secreted glycophosphoprotein which induces migration of mammary carcinoma cells, and has been implicated in the malignancy of breast carcinoma. Hepatocyte growth factor (HGF) induces cell migration of several mammary epithelial cell (MEC) lines, via activation of its cognate receptor (Met). This study examines the mechanism of OPN-induced MEC migration, in terms of the cell surface integrins involved and induction of the HGF/Met pathway. Three different MEC cell lines were used, representing different stages of tumor progression: 21PT, non-tumorigenic; 21NT, tumorigenic; non-metastatic; and MDA-MB-435, tumorigenic, highly metastatic. Human recombinant OPN was found to induce the migration of all three lines. OPN-induced migration of 21PT and 21NT cells was alphavbeta5 and beta1-integrin dependent, and alphavbeta3-independent, while that of MDA-MB-435 cells was alphavbeta3-dependent. HGF also induced migration of all three cell lines, and a synergistic response was seen to HGF and OPN together. The increased migration response to OPN was found to be associated with an initial increase in Met kinase activity (within 30 min), followed by an increase in Met mRNA and protein expression. OPN-induced cell migration is thus mediated by different cell surface integrins in MEC lines representing different stages of progression, and involves activation of the HGF receptor, Met.
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PMID:Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met). 1086 44

Gastric cancers producing alpha-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(-)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(-) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.
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PMID:High frequency of c-Met expression in gastric cancers producing alpha- fetoprotein. 1097 Nov 74

Using subtractive technology, we have generated metastasis-associated gene expression profiles for rat mammary and pancreatic adenocarcinomas. Several genes whose expression is thought to be related to tumor progression such as c-Met, urokinase-type plasminogen activator receptor, ezrin, HMG-1, oncomodulin, cathepsin, and caveolin were thereby isolated. Half of the metastasis-associated clones showed no significant homology to genes with known function. Notably, several of the metastasis-associated clones were also expressed in metastatic lines but not in nonmetastatic lines of other tumor models. Furthermore, in situ hybridization using selected clones documents the relevance of these results for human cancer because strong expression in tumor cells including metastases was detected in human colorectal cancer samples and, to a lesser extent, in mammary cancer samples. These data support the concept that tumors express a "metastatic program" of genes.
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PMID:Gene expression patterns associated with the metastatic phenotype in rodent and human tumors. 1124 67

To identify changes in gene expression with transformation and metastasis, we investigated differential gene expression in a squamous carcinoma model established in syngeneic mice. We used mRNA differential display (DD) to detect global differences and cDNA arrays enriched for cancer-associated genes using mRNA from primary keratinocytes, transformed Pam 212 squamous carcinoma cells, and metastases of Pam 212. After DD, 72 candidate cDNAs expressed primarily in transformed and metastatic cells were selected and cloned. Fifty-seven were detected, and 32 were confirmed to be differentially expressed by Northern blot analysis. mRNA expression profiles were also generated using a mouse cDNA array composed of 4000 elements representing known genes and expressed sequence tags plus the 57 DD candidate cDNAs detected by Northern analysis to facilitate data validation. cDNA array detected 76.9% of the differentially expressed mRNAs selected from DD and confirmed by Northern blot, whereas low-abundance mRNAs did not reach the threshold for detection by the lower-sensitivity array method. Clustering analysis of DD and array results from transformed and metastatic cells identified genes that exhibited decreased or increased expression with transformation and metastasis. Alterations in the expression of several genes detected during tumor progression were consistent with their functional activities involving growth (p21, p27, and cyclin D1), resistance and apoptosis (glutathione-S-transferase, cIAP-1, PEA-15, and Fas ligand), inflammation and angiogenesis [chemokine growth-regulated oncogene 1 (also called KC)], and signal transduction (c-Met, yes-associated protein, and syk). Strikingly, 10 of 22 genes in the cluster expressed in metastases have been associated with activation of the nuclear factor (NF)-kappaB signal pathway. The NF-kappaB-inducible cytokine Gro-1 was recently shown to promote tumor growth, metastasis, and angiogenesis of squamous cell carcinomas in vivo (Loukinova et al., Oncogene, 19: 3477-3486, 2000). The results demonstrate that early response genes related to NF-kappaB contribute to metastatic tumor progression. Comparison of cell lines and tumor tissue revealed a concordance of approximately 50% by array, and 70% for Northern-confirmed, metastasis-related genes. Functional genomic approaches comparing expression among cell lines and tumor tissue may promote a better understanding of the genes expressed by malignant and host cells during tumor progression and metastasis.
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PMID:Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-kappaB signal pathway. 1140 55

Tumour progression to the metastatic phenotype is mainly dependent on tumour cell invasiveness. Cell migration is a crucial step in this process. Here we investigate the effect of hepatocyte growth factor (HGF) on the induction of in vitro invasiveness of poorly aggressive Caco-2 colonic cancer epithelial cells. Invasion assays through a Matrigel barrier were performed. Proteases were assessed by zymography, reverse transcription-polymerase chain reaction and immunoblotting. Caco-2 cells were found to express HGF receptor but not HGF and to secrete several proteases, namely matrix metalloproteinase-1 (MMP-1), MMP-2, possibly MMP-9 and urokinase plasminogen activator (uPA). Exogenous HGF promoted invasiveness of Caco-2 cells through an artificial basement membrane matrix and enhanced their production of proteases. In addition, analyses of media at the end of invasion assays indicated that anti-HGF antibody inhibited protease production in parallel with cell invasion. The involvement of proteases in the HGF-induced invasion process was further investigated using either a synthetic general MMP inhibitor or neutralizing antibodies against MMPs or uPA. All components significantly inhibited HGF-promoted cell invasion. Moreover, specific inhibitors of PKCalpha/beta1 and PI3 kinase also decreased both HGF-promoted cell invasion and protease expression in invasion assay media. Thus, our findings provide evidence that the process of HGF-activated invasiveness of Caco-2 cells involves PI3 kinase and PKC and results from close association of two events, stimulation of cell motile activity and concomitant overproduction of proteases, which permits cell migration through a degraded extracellular matrix.
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PMID:Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. 1140 46

Currently, molecular markers offer the unique opportunity to identify occult metastasis in early stage cancer patients not otherwise detected with conventional staging techniques. To date, well-characterized molecular tumor markers to detect occult breast cancer cells in blood are limited. Because breast tumors are heterogeneous in tumor marker expression, we developed a "multimarker" reverse transcription-PCR assay combined with the highly sensitive electrochemiluminescence automated detection system. Breast cancer cell lines (n = 7), primary breast tumors (n = 25), and blood from normal donors (n = 40) and breast cancer patients [n = 65; American Joint Committee on Cancer (AJCC) stages I-IV] were assessed for four mRNA tumor markers: beta-human chorionic gonadotropin (beta-hCG), oncogene receptor (c-Met), beta 1-->4-N-acetylgalactosaminyl-transferase, and a tumor-associated antigen (MAGE-A3). None of the tumor markers were expressed in any normal donor bloods. Breast cancer cell lines and primary breast tumors expressed beta-hCG, c-Met, beta 1-->4-N-acetylgalactosaminyl-transferase, and MAGE-A3 mRNA. Of the 65 breast cancer patient blood samples assessed, 2, 3, 15, 49, and 31% expressed 4, 3, 2, 1, and 0 of the mRNA tumor markers, respectively. At least two markers were expressed in 20% of the blood specimens. The addition of a combination of markers enhanced detection of systemic metastasis by 32%. In patient blood samples, the MAGE-A3 marker correlated significantly with tumor size (P = 0.0004) and AJCC stage (P = 0.007). The combination of beta-hCG and MAGE-A3 mRNA markers correlated significantly with tumor size (P = 0.04), and the marker combination c-Met and MAGE-A3 showed a significant correlation with tumor size (P = 0.005) as well as AJCC stage (P = 0.018). A multimarker reverse transcription-PCR assay that correlates with known clinicopathological prognostic parameters may have potential clinical utility by monitoring tumor progression with a blood test.
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PMID:Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease. 1175 7

Hepatocyte growth factor (HGF), also known as a scatter factor, regulates a variety of biological activities including cell proliferation, survival, migration, and angiogenesis. Importantly, HGF and its receptor c-Met have been found to be associated with metastasis of human head and neck squamous cell carcinoma (HNSCC). Because anoikis resistance plays an important role in tumor progression and metastasis, here we examined whether HGF suppressed suspension-induced apoptosis (anoikis) in HNSCC cells, and if so, we assessed downstream signaling pathways mediated by HGF. We found that HNSCC cells underwent anoikis upon loss of matrix contact, whereas HGF provided protection against it. HGF-induced anoikis resistance was found to be dependent on both ERK and Akt signaling pathways. The inhibition of either ERK or Akt activation abolished HGF-mediated survival. Furthermore, we found that HGF did not activate NFkappaB transcription in HNSCC cells and that HGF-mediated anoikis resistance was independent of NFkappaB. Taken together, our results suggest that anoikis resistance induced by HGF may also play an important role in the progression and metastasis of HNSCC.
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PMID:Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B. 1199 87

Normal cells are dependent on exogenous, receptor-mediated growth stimulation for cell cycle entry and progression, providing a critical homeostatic mechanism regulating cellular proliferation. In contrast, tumor cells acquire some degree of growth signal autonomy, often through their ability to produce growth factors as well as their receptors (autocrine signaling). Recently, data have begun to emerge implicating heterotypic signaling between diverse cell types within a tumor in the genesis and progression of cancer; however, current experimental approaches in vivo have not adequately addressed this critical relationship. Here we used transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF), or its growth antagonist NK2, as genetically modified hosts for transplantation of tumor cells expressing their receptor, c-Met, to directly assess the contribution of heterotypic signaling to metastatic colonization. We demonstrate that metastatic potential under nonautocrine signaling conditions (i.e., where tumor cells expressing c-Met are transplanted into transgenic hosts producing HGF/SF) rivaled that observed under conditions of autocrine signaling (i.e., where tumor cells expressing both HGF/SF and c-Met are transplanted into wild-type hosts). HGF/SF and NK2 were not functionally equivalent in vivo. Attenuation of NK2-associated growth inhibition by the presence of an HGF/SF-Met autocrine loop uncovered a shift in metastatic site preference from lung to liver only in NK2-transgenic hosts, a qualitative behavioral alteration likely detectable only through the genetic approach used here. Our data demonstrate that growth factors not intrinsic to malignant cells can have profound effects on metastatic efficiency in vivo and provide experimental support of a role for heterotypic signaling in tumor progression.
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PMID:Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. 1201 77

The hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met and variants of the CD44 family of surface adhesion molecules, including CD44v6, have been implicated in cancer progression and metastasis. CD44 isoforms bearing heparin sulfate chains can bind to HGF/SF and facilitate its presentation to c-Met. Here, we demonstrate that HGF/SF-Met binding up-regulates the expression of CD44v6 in murine melanoma cells, serving to compensate for loss by internalization. c-Met-mediated CD44v6 up-regulation was achieved through transcriptional activation of the immediate early gene egr-1. Enhanced egr-1 expression was apparent at the level of RNA 40 min after exposure to HGF/SF, and Egr-1 protein was detectable between 1 and 2 h post-treatment. CD44v6 RNA levels were correspondingly elevated 2 h after HGF/SF exposure. HGF/SF induced egr-1 activation via the Ras>Erk1/2 pathway but not through either phosphatidylinositol 3'-kinase or protein kinase C. Binding of NK2, a naturally occurring splice variant of HGF/SF, to c-Met failed to induce either Egr-1 or CD44v6, accounting at least in part for its antagonistic behavior. We also identified an Egr-1-binding site in the mouse CD44 gene promoter that accounts for its responsiveness to HGF/SF in melanoma cells. The compensatory up-regulation of both c-Met and CD44v6 in response to HGF/SF has important implications with respect to strategies used by cancer cells to sustain stimulation of growth- and metastasis-promoting pathways associated with tumor progression.
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PMID:Hepatocyte growth factor/scatter factor induces feedback up-regulation of CD44v6 in melanoma cells through Egr-1. 1267 Sep 7

Infection with the human microbial pathogen Helicobacter pylori is assumed to lead to invasive gastric cancer. We find that H. pylori activates the hepatocyte growth factor/scatter factor receptor c-Met, which is involved in invasive growth of tumor cells. The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response. CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2. The H. pylori-induced motogenic response is suppressed and blocked by the inhibition of PLCgamma and of MAPK, respectively. Thus, upon translocation, CagA modulates cellular functions by deregulating c-Met receptor signaling. The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.
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PMID:Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. 1271 69


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