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

Tumor progression is a multi-step process that requires a sequential selection of specific malignant phenotypes. Met activation may induce different phenotypes depending on tumor stage: inducing proliferation and angiogenesis in primary tumors, stimulating motility to form micrometastases, and regaining the proliferation phenotype to form overt metastases. To study how HGF/SF-induced proliferative phenotypes switch to the invasive phenotype is important for understanding the mechanism of tumor progression and will provide an attractive target for cancer intervention and therapy.
 ...
PMID:HGF/SF-Met signaling in tumor progression. 1568 27

Hepsin, a type II transmembrane serine protease, is highly upregulated in prostate cancer and promotes tumor progression and metastasis. We generated a soluble form of hepsin comprising the entire extracellular domain to show that it efficiently converts single-chain hepatocyte growth factor (pro-HGF) into biologically active two-chain HGF. Hepsin activity was potently inhibited by soluble forms of the bi-Kunitz domain inhibitors HAI-1B (IC(50) 21.1+/-2.7 nM) and HAI-2 (IC(50) 1.3+/-0.3 nM). Enzymatic assays with HAI-1B Kunitz domain mutants (R260A and K401A) further demonstrated that inhibition was due to Kunitz domain-1. The results suggest a functional link between hepsin and the HGF/Met pathway, which may contribute to tumor progression.
 ...
PMID:Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. 1579 1

Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-alpha, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.
 ...
PMID:Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. 1616 66

Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
 ...
PMID:Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. 1682 72

Reactive oxygen species (ROS) are recently proposed to be involved in tumor metastasis which is a complicated processes including epithelial-mesenchymal transition (EMT), migration, invasion of the tumor cells and angiogenesis around the tumor lesion. ROS generation may be induced intracellularly, in either NADPH oxidase- or mitochondria-dependent manner, by growth factors and cytokines (such as TGFbeta and HGF) and tumor promoters (such as TPA) capable of triggering cell adhesion, EMT and migration. As a signaling messenger, ROS are able to oxidize the critical target molecules such as PKC and protein tyrosine phosphates (PTPs), which are relevant to tumor cell invasion. PKC contain multiple cysteine residues that can be oxidized and activated by ROS. Inactivation of multiple PTPs by ROS may relieve the tyrosine phosphorylation-dependent signaling. Two of the down-stream molecules regulated by ROS are MAPK and PAK. MAPKs cascades were established to be a major signal pathway for driving tumor cell metastasis, which are mediated by PKC, TGF-beta/Smad and integrin-mediated signaling. PAK is an effector of Rac-mediated cytoskeletal remodeling that is responsible for cell migration and angiogenesis. There are several transcriptional factors such as AP1, Ets, Smad and Snail regulating a lot of genes relevant to metastasis. AP-1 and Smad can be activated by PKC activator and TGF-beta1, respectively, in a ROS dependent manner. On the other hand, Est-1 can be upregulated by H2O2 via an antioxidant response element in the promoter. The ROS-regulated genes relevant to EMT and metastasis include E-cahedrin, integrin and MMP. Comprehensive understanding of the ROS-triggered signaling transduction, transcriptional activation and regulation of gene expressions will help strengthen the critical role of ROS in tumor progression and devising strategy for chemo-therapeutic interventions.
 ...
PMID:The signaling mechanism of ROS in tumor progression. 1716 Jul 8

In this age of targeted therapy, identification of molecular pathways that are deregulated in cancer will not only elucidate underlying tumorigenic mechanisms, but may also help to determine the classes of drugs that are used for treatment. In kidney cancer, a spectrum of histological subtypes exists that are characterized both by distinct molecular signatures and increasingly by distinct molecular pathways that are deregulated in each subtype. For example, the VHL/hypoxia pathway is well-known to be deregulated in clear cell renal cell carcinoma (RCC) whereas in papillary RCC activation of the HGF/Met pathway has been implicated. Additional molecular pathways, many not yet identified, may also be involved in the development of the different histologic subtypes. Moreover, differences in pathway activation may reflect differences in tumor progression and response to treatment. In this article, we describe an oncogenomic approach, based on integrative analysis of gene expression profiling data. In this approach, gene expression data is used to identify both cytogenetic abnormalities and molecular pathways that are deregulated in RCC. Ideally, predicted pathway abnormalities can be linked to predicted cytogenetic abnormalities to identify likely candidate genes. Although further cellular and functional studies are warranted to validate the computational models, development of such models in RCC have the potential to open up new avenues of molecular research and may have significant diagnostic and therapeutic implications.
 ...
PMID:Identification of deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomic approach based on gene expression profiling. 1732 20

Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering, morphogenesis, and survival of epithelial cells through activation of the MET tyrosine kinase receptor. HGF/SF and MET are involved in normal development and tumor progression of many tissues and organs, including the mammary gland. In order to find target genes of HGF/SF involved in its survival function, we used an oligonucleotide microarray representing 1,920 genes known to be involved in apoptosis, transcriptional regulation, and signal transduction. MCF-10A human mammary epithelial cells were grown in the absence of serum and treated or not with HGF/SF for 2 h. Total RNA was reverse-transcribed to cDNA in the presence of fluorescent Cy3-dUTP or Cy5-dUTP to generate fluorescently labeled cDNA probes. Microarrays were performed and the ratios of Cy5/Cy3 fluorescence were determined. The expression of three apoptotic genes was modified by HGF/SF, with A20 being upregulated, and DAXX and SMAC being downregulated. These changes of expression were confirmed by real-time quantitative PCR. According to current-knowledge, A20 is antiapoptotic and SMAC is proapoptotic, while a pro- or antiapoptotic function of DAXX is controversial. The fact that HGF/SF upregulates an antiapoptotic gene (A20) and downregulates a proapoptotic gene (SMAC) is in agreement with its survival effect in MCF-10A cells. This study identified novel apoptotic genes regulated by HGF/SF, which can contribute to its survival effect.
 ...
PMID:HGF/SF regulates expression of apoptotic genes in MCF-10A human mammary epithelial cells. 1738 62

Alterations in the c-Met/HGF system are frequently observed in various types of tumors and can directly influence tumor progression. In particular, the c-Met/HGF system can influence progression of lung tumors. The altered c-Met and HGF expression occurs in non-small-cell lung carcinomas. In this work we analyzed changes in c-Met and HGF expression in non-small-cell lung carcinomas by comparing expression levels with those in adjacent non-malignant tissues using semi-quantitative PCR. The c-Met transcript was detected in 50% of squamous cell carcinoma samples with an elevated level observed in 2 out of 25 cases (8%). HGF expression was detected only in two squamous cell carcinomas. At the same time, the c-Met transcript was observed in all 5 studied adenocarcinoma samples with an increased level compared to adjacent non- malignant tissue in 3 cases. HGF transcript was found in 2 adenocarcinoma samples. Therefore, c-Met rather than HGF transcript is frequently observed in non-small-cell lung carcinomas, especially in adenocarcinomas. According to the results of other studies, the c-Met transcript can serve as an indicator of the aggressive behavior and progression of non-small-cell lung carcinomas.
 ...
PMID:[c-Met and HGF expression in non-small-cell lung carcinomas]. 1759 53

The protooncogene c-met encodes the tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF). While overexpression of c-met is documented in many types of tumors, the mechanism of c-met regulation remains elusive. Here, we demonstrate Daxx as a repressor of c-met transcription. The expression of c-met is elevated in Daxx knockout mouse cells and is reversed by Daxx reconstitution. C-met promoter analysis of Daxx-/- cells reveled changes in chromatin acetylation, but not in DNA methylation. Daxx binds to the mouse c-met promoter and Daxx-binding region is sufficient for transcription repression, while HDAC2 is associated with c-met promoter mostly in Daxx+/+ cells, pointing to Daxx-dependent HDAC2 recruitment as a potential mechanism of c-met repression. HGF-induced cell mobility and invasion confirmed augmented activity of c-Met/HGF pathway in Daxx-/- cells. Finally, inverse correlation between Daxx and c-Met in cancer cell lines and in metastatic breast cancer specimens suggests potential function of Daxx as a c-met repressor during cancer progression.
 ...
PMID:Regulation of c-met expression by transcription repressor Daxx. 1795 15

Hepatocyte growth factor activator (HGFA) is a serine protease and a potent activator of prohepatocyte growth factor/scatter factor (pro-HGF/SF), a multifunctional growth factor that is critically involved in tissue morphogenesis, regeneration, and tumor progression. HGFA circulates as a zymogen (pro-HGFA) and is activated in response to tissue injury. Although thrombin is considered to be an activator of pro-HGFA, alternative pro-HGFA activation pathways in tumor microenvironments remain to be identified. In this study, we examined the effects of kallikrein 1-related peptidases (KLKs), a family of extracellular serine proteases, on the activation of pro-HGFA. Among the KLKs examined (KLK2, KLK3, KLK4 and KLK5), we identified KLK4 and KLK5 as novel activators of pro-HGFA. Using N-terminal sequencing, the cleavage site was identified as the normal processing site, Arg407-Ile408. The activation of pro-HGFA by KLK5 required a negatively charged substance such as dextran sulfate, whereas KLK4 could process pro-HGFA without dextran sulfate. KLK5 showed more efficient pro-HGFA processing than KLK4, and was expressed in 50% (13/25) of the tumor cell lines examined. HGFA processed by these KLKs efficiently activated pro-HGF/SF, and led to cellular scattering and invasion in vitro. The activities of both KLK4 and KLK5 were strongly inhibited by HGFA inhibitor type 1, an integral membrane Kunitz-type serine protease inhibitor that inhibits HGFA and other pro-HGF/SF-activating proteases. These data suggest that KLK4 and KLK5 mediate HGFA-induced activation of pro-HGF/SF within tumor tissue, which may thereafter trigger a series of events leading to tumor progression via the MET receptor.
 ...
PMID:Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases. 1822 92


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