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

Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named 'metastin'. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.
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PMID:Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. 1138 80

We have recently characterized a human bladder cancer cell line T24 and a more aggressive lineage related variant of it, T24T. To gain further insights, we have studied their metastatic ability in an in vivo model system. Results show that T24 forms significantly fewer [4/12 (1/11) mice had metastases with 1-2 lesions/mouse] metastasis in SCID/bg mice than T24T [14/14 (6/6) mice had metastases with a mean of 24-28 lesions/mouse]. To begin exploring the mechanisms underlying this difference, we evaluated the mRNA and protein expression levels of metastasis-suppressor genes, known to be important in the progression of other cancers, in our model of bladder cancer progression. A higher mRNA expression of BRMS1, a metastasis suppressor in breast cancer, was observed in T24 cells. In addition, RhoGDI2 mRNA expression was only observed in T24 when compared to T24T, suggesting that Rho activation might play a significant role in the metastatic cascade. However, a basal level mRNA expression of KISS1, described as metastasis suppressor in melanoma and breast, was observed in both the lines and had slightly higher expression in T24T. No difference of Nm23-H1, KAI1, MKK4/SEK1 and E-Cadherin protein levels were noted between these two lines. In summary, it appears that the T24/T24T paired cell lines constitute a useful model for the study of human bladder cancer metastasis that will allow both the discovery and mechanistic evaluation of genes potentially involved in this process.
Clin Exp Metastasis 2000
PMID:The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines. 1159 9

Metastatic disease is the most critical impediment to cancer patient survival. However, comparatively little is known concerning the intricate pathways which govern the complex phenotypes associated with metastasis. The KISS1 metastasis suppressor gene inhibits metastasis in both in vivo melanoma and breast carcinoma models. Despite its clear physiological activity, the mechanism of KISS1 remains unclear. Recent identification of a 54 amino acid peptide of KISS1, termed metastin or kisspeptin-54, and its cognate G-protein coupled receptor (hOT7T175, AXOR12, GPR54) have provided additional clues and avenues of research. While studies have attributed KISS1 with modulation of NFkappaB regulation, experiments with metastin and its receptor implicate MAP kinase pathways and also suggest the potential of autocrine, paracrine and endocrine roles. Impacts on motility, chemotaxis, adhesion and invasion have each been documented in disparate cell lines and conflicting observations require resolution. Nevertheless, mounting clinical evidence, particularly the loss of KISS1 in metastases, correlates KISS1 and metastin receptor expression with human tumor progression. Together, the data substantiate roles for these molecules in metastasis regulation.
Clin Exp Metastasis 2003
PMID:KISS1 metastasis suppression and emergent pathways. 1265 Jun 2

Melanoma is a highly metastatic cancer that accounts for the majority of skin cancer deaths. Unfortunately, very few improvements have been made during the last 20 years in the management of melanoma metastases, which is the major cause of melanoma deaths. Therefore, identification of molecular targets that can be exploited in the clinic to treat metastatic disease is desperately needed. The KISS1 metastasis suppressor gene has emerged as a promising molecular target for the management of metastatic disease. This review compiles data regarding the molecular and biochemical properties of KISS1 and its cognate receptor, focusing on the properties believed to be most pertinent to the use of KISS1 in the clinical setting. In addition, clinical data that supports KISS1 as having a dual role as a prognostic indicator and a therapeutic target for the management of metastatic disease will be highlighted.
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PMID:The KISS1 metastasis suppressor: mechanistic insights and clinical utility. 1614 58

The KiSS-1 gene encodes a 145 amino acid residue peptide that is further processed to a final peptide, metastin, a ligand to a G-coupled orphan receptor (OT7T175/AXOR12). KiSS-1 has been identified as a putative human metastasis suppressor gene in melanomas and in breast cancer cell lines. This study aimed to determine the expression and distribution of KiSS-1 and its receptor in human breast cancer tissues and to identify a possible link between expression levels and patient prognosis. Frozen sections from breast cancer primary tumours (matched tumour 124 and background 33) were immuno-stained with KiSS-1 antibody. RNA was reverse transcribed and analyzed by Q-PCR (standardized using beta-actin, and normalized with cytokeratin-19 levels). Levels of expression of KiSS-1 were higher in tumour compared to background tissues (3,124+/-1,262 vs 2,397+/-1,181) and significantly increased in node positive tumours compared to node negative (3,637+/-1,719 vs 2,653+/-1,994, P = 0.02). KiSS-1 expression was also increased with increasing grade and TNM status. There were no such trends with the KiSS-1 receptor. Expression of KiSS-1 was higher in patients who had died from breast cancer than those who had remained healthy (4,631+/-3,024 vs 2,280+/-1,403) whereas expression of the receptor was reduced (480+/-162 vs 195+/-134). Immunohistochemical staining showed increased expression of KiSS-1 in tumour sections. Insertion of the KiSS-1 gene into the human breast cancer cell line MDA-MB-231, resulted in cells that were significantly more motile and invasive in behaviour, with reduced adhesion to matrix, using respective assays. In conclusion, KiSS-1 expression is increased in human breast cancer, particularly in patients with aggressive tumours and with mortality. Over-expression of KiSS-1 in breast cancer cells result in more aggressive phenotype. Together, it suggests that KiSS-1 plays a role beyond the initial metastasis repressor in this cancer type.
Clin Exp Metastasis 2005
PMID:KiSS-1 expression in human breast cancer. 1632 Jan 13

Metastasis suppressor genes (MSGs) are defined by their ability to inhibit overt metastasis in a secondary organ without affecting tumor growth at the primary site. Over 20 MSGs have been confirmed in vivo. This class of genes is only unified by their capacity to suppress metastasis, as they encode for proteins with a wide range of biochemical activities that are components of a variety of signaling pathways. In addition, metastasis suppressors impinge upon different stages of the metastatic cascade to manifest their suppressive effects. The MSGs KISS1, KAI1, MKK4/7 and Nm23-H1 promote tumor dormancy at the metastatic site, since tumor cells with induced expression of these MSGs disseminate, but do not form overt metastases in the secondary organ throughout the duration of a metastasis assay. Evidence suggests that KISS1 triggers dormancy in solitary, metastatic tumor cells by causing growth arrest of solitary cells at the secondary site. KAI1 induces growth arrest prior to extravasation by binding a vascular endothelial cell surface marker. MKK4, MKK7 and Nm23-H1 appear to promote dormancy of micrometastatic colonies, after disseminated tumor cells have undergone several rounds of proliferation. Other MSGs may also function in tumor dormancy, but so far their role has not been fully elucidated. Therapeutic approaches that either mimic the effects of MSGs or re-establish MSG expression in metastatic lesions may hold promise for the establishment or maintenance of dormancy.
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PMID:The role of metastasis suppressor genes in metastatic dormancy. 1883 4

Metastin, which is a 54-residue peptide coded by KiSS-1 gene, is an endogenous ligand to a G-protein-coupled receptor GPR54. Metastin suppresses a malignant tumor to metastasize and regulates secretion of gonadotropine releasing hormone. Physiological action of metastin has been focused on in oncology. It is reported that less KiSS-1 gene and more hOT7T175 gene which codes GPR54 are expressed in pancreatic cancers than in normal pancreatic tissues; however, there is no study that investigates the relationship between clinicopathological characteristics and plasma metastin concentration in pancreatic cancer patients. The purpose of this study was to investigate the relationship between plasma metastin-like immunoreactive substance (LI) levels and clinical characteristics in pancreatic cancer patients. Thirty-three patients with pathologically confirmed pancreatic cancer before or just after treatments and 24 healthy volunteers were included in the study. Patients were grouped according to the International Union Against Cancer TNM classification. Plasma metastin-LI was measured by enzyme immunoassay. The plasma metastin-LI levels of cancer patients were significantly higher when compared with healthy volunteers. Significant relationship was not found between the plasma metastin-LI levels and the clinicopathological factors such as tumor size, invasion, lymph node metastasis and distant metastasis. The plasma metastin levels may be a significant biomarker to predict the presence of pancreatic cancer and could be used in pancreatic cancer screening.
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PMID:Clinical significance of plasma metastin level in pancreatic cancer patients. 1921 44

Metastasis suppressors and other regulators of cell motility play an important role in tumor invasion and metastases. We previously identified that activation of the G protein coupled receptor 54 (GPR54) by the metastasis suppressor metastin inhibits cell migration in association with overexpression of Regulator of calcineurin 1 (RCAN1), an endogenous regulator of calcineurin. Calcineurin inhibitors also blocked cell migration in vitro and RCAN1 protein levels were reduced in nodal metastases in thyroid cancer. The purpose of the current study was to determine directly if RCAN1 functions as a motility suppressor in vitro. Several cancer cell lines derived from different cancer types with different motility rates were evaluated for RCAN1 expression levels. Using these systems we determined that reduction of endogenous RCAN1 using siRNA resulted in an increase in cancer cell motility while expression of exogenous RCAN1 reduced cell motility. In one cell line with a high migratory rate, the stability of exogenously expressed RCAN1 protein was reduced and was rescued by treatment with a proteasome inhibitor. Finally, overexpression of RCAN1 was associated with an increase in cell adhesion to collagen IV and reduced calcineurin activity. In summary, we have demonstrated that the expression of exogenous RCAN1 reduces migration and alters adhesion; and that the loss of endogenous RCAN1 leads to an increase in migration in the examined cancer cell lines. These results are consistent with a regulatory role for RCAN1 in cancer cell motility in vitro.
Clin Exp Metastasis 2009
PMID:Regulator of calcineurin 1 modulates cancer cell migration in vitro. 1930 9

KISS1 was first discovered as a metastasis suppressor, but also plays crucial roles in the onset of puberty. The KISS1 gene encodes a secreted protein of 145 amino acids that exhibits no sequence similarity with any known proteins. KISS1 protein is proteolytically processed to generate a number of so-called kisspeptins (KP), the most well characterized is known as KP-54 or metastin. KP-54 is carboxy-terminally amidated and binds to and activates the KISS1 receptor (KISS1R). The current studies were undertaken in order to determine structure of KP-54 using nuclear magnetic resonance and circular dichroism. KP-54 is mostly disordered both in water and in trifluoroethanol/water mixed solvent, with no structural motifs. In sodium dodecyl sulfate micelles, KP-54 remains mostly disordered except for a small increase in helical propensity (from 3.7% in water to 9.9% in micelles). Despite this apparent lack of structure, KP-54 is biologically active. The intrinsic disorder of KP-54 may confer advantages in its ability to recognize and bind a wide range of target proteins.
Clin Exp Metastasis 2009
PMID:Nuclear magnetic resonance and circular dichroism study of metastin (Kisspeptin-54) structure in solution. 1930 66

Kisspeptin and its receptor, GPR54, are major regulators of the hypothalamic-pituitary-gonadal axis as well as regulators of human placentation and tumor metastases. GPR54 is a G(q/11)-coupled G protein-coupled receptor (GPCR), and activation by kisspeptin stimulates phosphatidy linositol 4, 5-biphosphate hydrolysis, Ca(2+) mobilization, arachidonic acid release, and ERK1/2 MAPK phosphorylation. Physiological evidence suggests that GPR54 undergoes agonist-dependent desensitization, but underlying molecular mechanisms are unknown. Furthermore, very little has been reported on the early events that regulate GPR54 signaling. The lack of information in these important areas led to this study. Here we report for the first time on the role of GPCR serine/threonine kinase (GRK)2 and beta-arrestin in regulating GPR54 signaling in human embryonic kidney (HEK) 293 cells, a model cell system for studying the molecular regulation of GPCRs, and genetically modified MDA MB-231 cells, an invasive breast cancer cell line expressing about 75% less beta-arrestin-2 than the control cell line. Our study reveals that in HEK 293 cells, GPR54 is expressed both at the plasma membrane and intracellularly and also that plasma membrane expression is regulated by cytoplasmic tail sequences. We also demonstrate that GPR54 exhibits constitutive activity, internalization, and association with GRK2 and beta- arrestins-1 and 2 through sequences in the second intracellular loop and cytoplasmic tail of the receptor. We also show that GRK2 stimulates the desensitization of GPR54 in HEK 293 cells and that beta-arrestin-2 mediates GPR54 activation of ERK1/2 in MDA-MB-231 cells. The significance of these findings in developing molecular-based therapies for treating certain endocrine-related disorders is discussed.
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PMID:Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. 1984 37


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