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)

Recent data have proposed that transcription of the KAI1 metastasis suppressor gene is directly mediated by p53 and that loss of KAI1 expression in advanced prostate cancer is simply due to loss of p53 function after mutation. To investigate this possibility, we have examined KAI1 mRNA (by in situ hybridisation) and p53 protein expression (by immunohistochemistry) as an indicator of wildtype or mutant p53, in a series of 77 paraffin-embedded prostate tissue samples, including post-mortem normal prostates (2), benign prostatic hyperplasia (10), localised cancer (grades 4-6, 25; grades 7-9, 21) and prostate-derived bony metastases (19). Overall, we confirmed that expression of KAI1 mRNA decreased from normal tissue, through localised cancer to bony metastases (P=0.055, tending to significance), while levels of p53 staining significantly increased with cancer progression (P=0.046). These were consistent with the possibility that loss of p53 function might be responsible for loss of KAI1 mRNA. However, by close examination of KAI1 and p53 in adjacent tissue sections, we found no correlation between decreased levels of KAI1 mRNA and overexpression of p53 protein (P=0.497). In addition, high levels of KAI1 mRNA could be identified in samples irrespective of p53 staining. Our data suggest that mutation of p53 is independent of the loss of KAI1 mRNA, and do not support a role for p53 in regulating the expression of KAI1.
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PMID:Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression. 1280 79

Here we describe the isolation of C33/CD82/KAI1 in a screen for apoptosis-inducing genes. C33 is a gene that is downregulated in many metastatic tumor cells and the expression of which can attenuate the process of metastases formation in a variety of tumors. In accordance, we observed cell death induction by C33 in many different cell types. C33 seems to promote cell death by the generation of reactive oxygen intermediates (ROIs). These ROIs, however, are not derived from the mitochondrial respiratory chain as in most other scenarios leading to apoptosis. We observed that C33 renders cells sensitive to ROIs by causing the specific release of the intracellular antioxidant glutathione (GSH) from cells. Moreover, C33 activates the GTPase Cdc42, which mediates GSH release and apoptosis induction and allows to detect the formation of ROIs.
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PMID:The metastasis suppressor gene C33/CD82/KAI1 induces apoptosis through reactive oxygen intermediates. 1459 53

CD82 (KAI1) and CD63 (ME491) are highly glycosylated proteins which belong to the transmembrane 4 superfamily (TM4SF). CD82 has been implicated as a possible prostate cancer metastasis suppressor gene, whereas CD63 is involved in the progression of human melanoma cancer. Down-regulation of both CD82 and CD63 expression has been associated with the metastatic potential of several solid tumors. Currently, information is lacking on the role of CD82 and CD63 during thyroid carcinogenesis. The aim of this study was to determine whether the expression of CD82 and CD63 is a useful prognostic indicator in patients with thyroid carcinoma. The expression of CD82 and CD63 was analysed by reverse transcriptase-PCR (RT-PCR) and immunohistochemistry in benign goiter (n=12) and 75 primary thyroid carcinoma tissue specimens (PTC: 33, FTC: 24, UTC: 18) out of which 36 were non-metastasized primary tumors and 39 were metastasized tumors (regional lymph node and/or distant metastases). All of the benign goiter tissues showed CD82 expression. By contrast, a significant decrease in CD82 mRNA and protein levels was detected in carcinoma tissues as compared to benign goiter tissues (p<0.001). A similar down-regulation was observed in metastasized tumor tissues when compared with non-metastasized tumors (all p<0.05). CD82 expression was correlated with pTNM status of differentiated and undifferentiated thyroid tumor and the pathologic stage of differentiated thyroid tumor. In contrast to CD82, CD63 mRNA and protein expression was unchanged in all thyroid carcinomas. Benign goiter tissues showed weak expression of CD63. There were no significant correlation between CD63 mRNA/protein expression and any clinical/pathological parameters. Our results support the hypothesis that down-regulation of CD82 expression may reflect an increased in vivo metastatic potential of thyroid cancer cells. CD82 may serve as a prognostic marker of metastasis in thyroid cancer. Constitutive expression of CD63 may indicate that this factor does not play a direct role in thyroid carcinogenesis.
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PMID:CD82, and CD63 in thyroid cancer. 1537 77

A panel of markers, selected for the suspected bladder cancer relevance of their corresponding genes, were explored for their expression and subcellular location in urinary bladder tissue. The expression in normal urothelium, in non-metastasised transitional cell carcinomas (TCC), and in primary metastasised TCC with corresponding metastases was mapped. Potential associations between the proteins were identified. The observations were then combined in a set of hypotheses aimed at further hypothesis testing. Membranous ERBB4 and cytoplasmic p21RAS were downregulated in carcinoma cells compared with normal urothelium cells. FGFR3 was translocated from the cytoplasm to the nucleus. ERBB2 was translocated to the membrane and seemingly upregulated in one subgroup and conversely downregulated in another. EGFR, KAI1 and possibly PTEN revealed increased membranous immunoreactivity in non-metastasised tumours. The metastases showed decreased nuclear FGFR3 and membranous PTEN staining compared with corresponding primary tumours. EGFR expression was positively correlated with the expression of PTEN and FGFR3. The expression of ERBB2 was negatively correlated with p21RAS expression. According to our results, bladder carcinogenesis comprises FGFR3 translocation to the nucleus, upregulation of EGFR, ERBB2, KAI1 and PTEN; downregulation of p21RAS; and translocation of EGFR, ERBB2, and possibly PTEN to the membrane. Our results support the hypotheses regarding PTEN and KAI1 functioning as tumour suppressors in bladder cancer. EGFR and KAI1 may discriminate between non-metastasised and metastasised cancers. A complex network of associations between the factors is suggested.
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PMID:Protein networking in bladder cancer: immunoreactivity for FGFR3, EGFR, ERBB2, KAI1, PTEN, and RAS in normal and malignant urothelium. 1729 Mar 45

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

Conventional therapies still remain less effective for metastasis of lung cancer, thus leading to a poor prognosis for this disorder. Although the processes involved in metastasis have not yet been clearly elucidated, our previous studies have shown that higher expression levels of MRP-1/CD9 and KAI1/CD82 in cancer cells are significantly correlated with less metastatic potency. To determine whether the gene transfer of these tetraspanins into lung tumor cells may be a useful strategy to regulate metastasis, we adopted an orthotopic lung cancer model produced by the intrapulmonary implantation of Lewis lung carcinoma (LLC) cells and evaluated the metastatic growth in the mediastinal lymph nodes using two different methods of gene delivery as follows: (a) the implantation of LLC cells preinfected with adenovirus encoding either MRP-1/CD9 cDNA, KAI1/CD82 cDNA, or LacZ gene into the mouse lung and (b) the intratracheal administration of these adenoviruses into the mice orthotopically preimplanted with LLC cells. In both cases, we found that the delivery of either MRP-1/CD9 or KAI1/CD82 cDNA dramatically reduced the metastases to the mediastinal lymph nodes in comparison with those of LacZ gene delivery, without affecting the primary tumor growth at the implanted site. These results reemphasize the important role of MRP-1/CD9 and KAI1/CD82 in the suppression of the metastatic process and also show the feasibility of gene therapy when using these tetraspanins for lung cancer to prevent metastasis to the regional lymph nodes. This strategy may therefore be clinically applicable as a prophylactic treatment to suppress the occurrence of lymph node metastasis.
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PMID:Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model. 1730 16

Metastasis is the primary cause of death in cancer patients. However, the molecular mechanism of the metastatic process is poorly understood because it involves multiple steps with a high degree of complexity. A critical step for successful establishment of secondary colonization is the hematogenous dissemination of malignant cells. During this process, the attachment of cancer cells to the endothelial cells on microvasculature is considered to be an essential step and many adhesion molecules as well as chemokines have been found to be involved in this process. This interaction of cancer-endothelial cell is considered not only to determine the physical site of metastasis, but also to provide the necessary anchorage to facilitate tumor cell extravasation. However, recent evidence indicates that this interaction also serves as a host defense mechanism and hinders the process of metastasis. The tumor metastases suppressor gene, KAI1, has been known to block metastatic process without affecting the primary tumor growth, and this protein has been found to be able to bind to the chemokine receptor, Duffy antigen receptor for chemokines (DARC), which is expressed on endothelial cells. Importantly, this interaction markedly induces senescence of tumor cells. This novel finding is not only significant in the context of molecular dissection of metastatic process but also in the therapeutic implication to develop drugs inhibiting metastasis.
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PMID:Tumor-endothelial cell interactions: therapeutic potential. 1749 48

Dominant negative (DN) mutations of tumor suppressor p53 (TP53) are clinically associated with cancer progression and metastasis of endometrial malignancy. To investigate the DN effect on tumor migration and invasion, we generated cells that stably co-expressed wild-type (wt) and R273H DN mutant TP53 (273H cells), and wt and R213Q recessive mutant TP53 (213Q cells), by transfection in endometrial cancer cells HHUA that expressed wt p53. R273H, but not R213Q, repressed wt p53-stimulated transcription of p21, Bax, and MDM2. 273H cells also showed markedly increased in vitro invasion and migration potentials, and displayed reduced Maspin, PAI-1, and KAI1 mRNA expressions as compared with 213Q and wt cells. The induction of wt p53 function by use of Adriamycin resulted in the inhibition of the invasion/migration capacity in association with the up-regulation of p53 target genes to a far greater degree in 213Q and wt cells than in 273H cells. R273H expression in p53-null cancer cell SK-OV-3 and Saos-2 did not significantly affect cell invasion and migration activities. Taken together, these results suggest that transdominance of R273H mutant over wt p53 rather than a gain-of-function promotes tumor metastasis by increasing invasion and migration in HHUA cells.
Clin Exp Metastasis 2007
PMID:p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells. 1763 7

Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.
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PMID:The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. 1803 95

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


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