Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor metastases suppressor protein KAI1/CD82 is capable of blocking the tumor metastases without affecting the primary tumor formation, and its expression is significantly down-regulated in many types of human cancers. However, the exact molecular mechanism of the suppressor function of KAI1 remains elusive. Evidence from our laboratory supports a model in which tumor cells dislodge from the primary tumor and intravasate into the blood or lymphatic vessels followed by attachment to the endothelial cell surface whereby KAI1 interacts with the Duffy antigen receptor for chemokines (DARC) protein. This interaction transmits a senescent signal to cancer cells expressing KAI1, whereas cells that lost KAI1 expression can proliferate, potentially giving rise to metastases. Our model of the mechanism of action of KAI1 shows that metastasis suppressor activity can be dependent on interaction with host tissue and explains how KAI1 suppresses metastasis without affecting primary tumor formation. Taken together, in vitro and in vivo studies identify the KAI1-DARC interaction as a potential target for cancer therapy.
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PMID:Interaction of Duffy antigen receptor for chemokines and KAI1: a critical step in metastasis suppression. 1730 76

Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype.
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PMID:Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. 1740 39

The breast cancer metastasis suppressor 1 (BRMS1) gene has been shown to suppress metastasis without affecting the growth of the primary tumor in mouse models. It has also been shown to suppress the metastasis of tumors derived from breast, melanoma, and, more recently, ovarian carcinoma (see ref 1). However, how BRMS1 exerts its metastasis suppressor function remains unknown. To shed light into its metastatic mechanism of action, the sensitive 2D-DIGE analysis coupled with MS has been used to identify proteins differentially expressed by either overexpressing (Mel-BRMS1) or silencing BRMS1 (sh635) in a melanoma cell line. After comparison of the protein profiles from WT, Mel-BRMS1, and sh635 cells, 79 spots were found to be differentially expressed. Mass spectrometry analysis allowed the unambiguous identification of 55 polypeptides, corresponding to 43 different proteins. Interestingly, more than 75% of the identified proteins were down-regulated in Mel-BRMS1 cells compared to WT. In contrast, all the identified proteins in sh635 cells extracts were up-regulated compared to WT. Most of the deregulated proteins are involved in cell growth/maintenance and signal transduction among other cell processes. Six differentially expressed proteins (Hsp27, Alpha1 protease inhibitor, Cofilin1, Cathepsin D, Bone morphogenetic protein receptor2, and Annexin2) were confirmed by immunoblot and functional assays. Excellent correlation was found between DIGE analysis and immunoblot results, indicating the reliability of the analysis. Available evidence on the reported functions of the identified proteins supports the emerging role of BRMS1 as negative regulator of the metastasis development. This work opens an avenue for the molecular mechanisms' characterization of metastasis suppressor genes with the aim to understand their roles.
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PMID:Proteomics-based strategy to delineate the molecular mechanisms of the metastasis suppressor gene BRMS1. 1799 38

Cancer metastasis is a complex, dynamic process that begins with dissemination of cells from the primary tumor and culminates in the formation of clinically detectable, overt metastases at one or more discontinuous secondary sites. Evidence from in vivo video microscopy as well as PCR and immunohistochemical studies suggest that cancer cell dissemination is an early event in tumor progression and that cells may persist in a potentially dormant state for a prolonged period. Similarly, the mechanisms by which these disseminated cells initiate growth and complete the process of metastatic colonization remain largely unknown. Understanding signal transduction pathways regulating this final step of metastasis is therefore critical for successful clinical management. While genetic mutations or epigenetic changes may be required for a cell or group of cells to separate and survive distant from the primary tumor, the microenvironment within secondary tissues plays a substantial role in influencing whether disseminated cells survive and proliferate. Our work is focused on using metastasis suppressor proteins to gain insight into why the majority of disseminated cells, which should be fully malignant, do not proliferate immediately at secondary sites. The translational goal of this work is to identify targets for inhibiting metastatic growth and prolonging disease-free survival.
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PMID:Using metastasis suppressor proteins to dissect interactions among cancer cells and their microenvironment. 1804 62

TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis.
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PMID:TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. 1807 67

Metastatic dissemination represents a leading cause of death in cancer patients. Elucidating the mechanisms of the metastatic process is therefore essential to control it. Since 1988, when the NME (NM23) gene was discovered, several genes specifically suppressing the metastatic potential of tumor cells, have been identified. These metastasis suppressor genes, which exhibit a reduced expression in metastatic tumor cells, are defined by their capacity to suppress metastatic dissemination in vivo without inhibiting primary tumor growth when transfected into metastatic cell lines and injected into experimental animals. Their decreased expression in a subset of human tumor cohorts is associated with a high metastatic potential, thus confirming the data obtained in experimental models. Most of these genes affect key signal transduction pathways, including mitogen-activated protein kinases, Rho-GTPases and G-protein-coupled receptors. These signaling categories control cell-cell and cell-matrix interactions, which are important in monitoring adhesion, invasion and migration properties of metastatic tumor cells. Reduced expression of metastasis suppressor genes is most often due to epigenetic mechanisms, suggesting that their re-expression could constitute a new anti-metastatic therapy. In this paper, we review the literature on metastasis suppressor genes, with a particular focus on NM23.
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PMID:[NM23 and metastasis suppressor genes: update]. 1815 14

Although metastatic spread is the most frequent cause of deaths in cancer patients, there are very few drugs specifically targeting this process. Bases for a new antimetastatic drug discovery strategy are weak because a great number of unknowns characterizes the whole understanding of the metastatic cascade mechanisms. Moreover, the current experimental models are too simplistic and do not account for the complexity of the phenomenon. Some targets have been identified but too few are validated. Among them, metastasis suppressor genes seem to be the most promising. In spite of this, during the last years, a dozen of molecules which fulfill the definition of a specific metastatic drug, namely that inhibit metastases without altering growth of the primary tumor (which can be eradicated by surgery), have been identified and tried out to assess the proof of the concept. The continuation of this effort would be more efficient if the objectives were defined more precisely. It is particularly important to distinguish molecules aimed at preventing metastic cell spreading at the primary tumour early stage and molecules which have to induce a regression of established metastases or to inhibit the transition from disseminated occult tumour cells to dormant micrometastasis. This second goal is a priori more relevant in the current clinical setting where detection of the early metastatic spread is very difficult, and therefore it should focus a greater effort of the scientific community.
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PMID:[Metastatic spread: mechanisms and therapies]. 1815 75

In this study, we analyzed the effect of the metastasis suppressor CD82/KAI-1, a member of the tetraspanin superfamily, on intercellular adhesion on cancer cells. The newly established invasion assay and the cell aggregation assay revealed that CD82 strengthens E-cadherin-mediated intercellular adhesion. Interestingly, ectopic expression of CD82 stabilized E-cadherin/beta-catenin complex formation. Furthermore, CD82 reduced tyrosine phosphorylation of beta-catenin on HGF stimulation. Taken together, CD82 may stabilize or strengthen E-cadherin-dependent intercellular adhesion by regulating beta-catenin-mediated signal transduction on cancer cells, and consequently, prevent cancer cells from seceding from the primary tumor site.
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PMID:A novel function of CD82/KAI-1 on E-cadherin-mediated homophilic cellular adhesion of cancer cells. 1839 72

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, as it can induce apoptosis specifically in tumor cells but not in normal cells. Although earlier mouse tumor studies revealed a strong tissue dependency of TRAIL and its death receptor in suppressing primary tumorigenesis or experimental metastases, we recently found that TRAIL-R inhibits lymph node metastases without affecting primary tumor formation in a mouse model of multistage skin tumorigenesis. This finding uncouples the role of TRAIL in primary tumorigenesis from metastasis formation, likely by sensitization of previously TRAIL-resistant tumor cells upon detachment, an early step required for metastasis formation. Therefore, TRAIL-R is a novel metastasis suppressor, suggesting that TRAIL-related tumor therapy might be most effective in primary tumors and early metastatic cancers, before selection for TRAIL resistance occurs.
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PMID:Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: implications for TRAIL-based therapy in humans? 1867 22

Nm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.
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PMID:Clinical-translational approaches to the Nm23-H1 metastasis suppressor. 1869 18


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