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)

Transmembrane 4 superfamily (TM4SF) is a recently described gene family, and TM4SF members are known to play roles in the signal transduction pathways and to regulate cell activation, development, proliferation, and motility. MRP-1/CD9, KAI1/CD82, and ME491/CD63, members of the TM4SF, have been reported to suppress tumor progression or metastasis. Previously, we showed that MRP-1/CD9 suppressed cell motility and metastatic potential to lungs. Moreover, reduction of MRP-1/CD9 and KAI1/CD82 gene expression was found to be a factor in a poor prognosis for patients with non-small cell lung cancer. However, among TM4SF, CD151 is identical to an existing gene, PETA-3, which may promote tumor metastasis of malignant cells, and its expression may be involved in the malignant progression of cancer. The function of CD151 is opposite that of the metastasis suppressor genes, MRP-1/CD9 and KAI1/CD82. On the basis of these results, we used reverse transcription-PCR and immunohistochemical techniques for a retrospective study of CD151 gene expression in tumor tissues from 145 lung cancer patients; 72 tumors were stage I, 29 stage II, 27 stage IIIA, and 17 stage IIIB. Whereas 86 patients had tumors positive for the CD151 gene, 59 had tumors that were negative for the CD151 gene. The overall survival rate of patients with CD151-positive tumors was much lower than that of CD151-negative patients (51.9% versus 73.1%; P = 0.013). Our findings suggest that high CD151 gene expression in lung cancer may be associated with a poor prognosis. Assessment of CD151 could be instrumental for improvements in lung cancer diagnosis and therapies.
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PMID:Clinical significance of CD151 gene expression in non-small cell lung cancer. 1175 9

Current diagnostic methods in prostate cancer are lacking in their ability to predict individual patient outcome which highlights the need for more sensitive prognostic markers. Biological markers are seen as attractive and relevant candidates in current efforts to improve prognostic methods. Since metastasis is the most important component of cancer progression and mortality, markers which are able to predict the likely acquisition of the metastatic phenotype, before the onset of metastases, would be extremely useful clinically. This review outlines various metastasis suppressor genes and metastasis promoters which might have potential prognostic use in prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 62-65
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PMID:Prostate cancer: are new prognostic markers on the horizon? 1249 1

The metastasis suppressor gene nm23 located on chromosome 17 might be one of the targets in deletions of chromosome 17. In this study, we analyzed the expression of nm23 and chromosome 17 aberrations in gastric cancer and assessed their clinicopathological and prognostic significance. In 103 gastric cancer patients, we examined nm23 expression by immunohistochemistry and detected chromosome 17 aberrations by fluorescence in situ hybridization. There was a significant difference in the expression of nm23 among differentiated histologic types (well > moderately > poorly) (p < 0.01). Negative expression of nm23 correlated with depth of invasion (p < 0.01), lymph node metastasis (p < 0.05), lymphatic invasion (p < 0.05), venous invasion (p < 0.05), poor prognosis (p < 0.05), and chromosome 17 loss (p < 0.05). Chromosome 17 aberrations broadly correlated with clinicopathological variables and were associated with poor prognosis (p < 0.05). Univariate analyses identified nm23 (p < 0.05), chromosome 17 aberrations (p < 0.05), tumor size (p < 0.01), depth of invasion (p < 0.0001), lymph node metastasis (P < 0.001), hepatic metastasis (p < 0.01), peritoneal dissemination (p < 0.01), and lymphatic invasion (p < 0.01) as significant prognostic factors. Multivariate analysis showed that expression of nm23 and chromosome 17 aberrations were not independent prognostic indicators. Our results indicate that negative expression of nm23 and chromosome 17 numerical aberrations correlate with tumor progression and poor prognosis but are not independent prognostic indicators.
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PMID:Clinical significance of nm23 expression and chromosome 17 numerical aberrations in primary gastric cancer. 1251 18

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.
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PMID:KISS1 metastasis suppression and emergent pathways. 1265 Jun 2

Drg-1 was previously identified (N. van Belzen et al., Lab. Investig., 77: 85-92, 1997) as a gene that was up-regulated by the induction of differentiation in a colon carcinoma cell line in vitro. Subsequently, this gene was found to be regulated by several factors including hypoxia, androgen, p53, and N-myc. Recently, Drg-1 has also been shown to be involved in tumor progression in animals, although the clinical significance of its involvement remains to be investigated. To clarify the functional role of Drg-1 in prostate cancer, we examined a clinical archive of cancer specimens for the expression of Drg-1 by immunohistochemistry. We found that the expression of Drg-1 had a significant inverse correlation with the Gleason grading and the overall survival rate of patients. In particular, the gene expression in patients with lymph node or bone metastasis was significantly reduced as compared with those with localized prostate cancer, suggesting that the function of Drg-1 is negatively involved in metastatic progression of the disease. To further clarify the function of this gene in the advancement of prostate cancer, a spontaneous metastasis assay was performed in a severe combined immunodeficient (SCID) mouse model. We found that Drg-1 almost completely inhibited lung colonization of highly metastatic prostate cancer cells without affecting the growth of the primary tumors. These results strongly suggest that Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker.
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PMID:The Drg-1 gene suppresses tumor metastasis in prostate cancer. 1270 52

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. Thus, in order to understand the process of acquisition of metastatic phenotypes in cancer cells, it is indispensable to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells. For this reason, we have been searching for genes that are preferentially altered in metastatic lung cancer cells and have activities to regulate their metastatic potentials. In lung cancer, both the p16INK4A/RB and p53 genes are frequently inactivated and are critical determinants for the regulation of cell growth and apoptosis. However, it still remains unclear whether these genes are also involved in the regulation of metastatic potential in lung cancer cells. Recently, we identified a novel myosin family gene, MYO18B, from the chromosome 22q12.1 region which shows frequent loss of heterozygosity in advanced lung cancer, and we found that this gene is inactivated in approximately 50% of lung cancers by deletions, mutations and methylation. Furthermore, restoration of MYO18B expression suppressed anchorage-independent growth of lung cancer cells. Thus, it was indicated that the MYO18B gene is a strong candidate for a metastasis suppressor gene of human lung cancer. Further functional and biological studies of the MYO18B gene will help us understand the molecular pathway of human lung cancer progression.
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PMID:Genetic alterations responsible for metastatic phenotypes of lung cancer cells. 1274 77

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

Activating mutations of Ras have been implicated in approximately 30% of human cancers. In every case, the biochemical consequence of such mutations is to disrupt the GTPase activity of Ras and to render Ras resistant to the actions of GTPase activating proteins. Consequently, oncogenic Ras mutants are "locked" in a GTP-bound active state. We detected a potent activity in Escherichia coli extract that can efficiently convert mutationally activated GTP-bound Ras to the inactive GDP-bound form. Purification of the protein responsible for this activity led to the identification of the enzyme nucleoside diphosphate kinase (Ndk). The human orthologue of Ndk is the NM23 metastasis suppressor, which we found to exhibit a similar activity. Purified Ndk effectively inactivates several of the oncogenic forms of Ras that are seen frequently in human cancers, including RasD12, the most commonly detected Ras mutation. Significantly, Ndk does not detectably affect wild-type Ras or an activated form of the Ras-related Rho GTPase. These results demonstrate that it is possible, through biochemical means, to specifically inactivate oncogenic Ras as a potential therapeutic approach to tumors that harbor Ras mutations. Moreover, the results suggest that the loss of NM23 expression that is commonly observed during tumor progression could lead to increased potency of oncogenic Ras proteins.
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PMID:Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. 1287 11

The multistep process of carcinogenesis implies the accumulation of multiple molecular defects. Alteration of tumor suppressor and metastasis suppressor genes are the important steps. Increasing experimental evidence indicates that decreased expression of tumor-metastasis/suppressor genes and gene products are involved in the progression of a variety of human malignancies. In the present study, we have extended this analysis to non-small cell lung carcinomas (NSCLC). The expression and prognostic significance of the tumor suppressor gene PTEN and metastasis suppressor genes nm23-H1 and KAI-1 was evaluated in NSCLCs. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissues from 53 bronchogenic adenocarcinomas and 51 squamous cell carcinomas using monoclonal antibodies against PTEN, nm23H-1, and KAI-1 proteins. Immunohistochemical results were correlated with tumor stage, grade, lymph nodes positivity, metastasis, and patient survival. Significant co-expression of PTEN, nm23-H1 and KAI-1 was observed in NSCLC (P<.001 to .002). The immunohistochemical expression of these proteins was significantly higher in stages 1 and 2 compared with stages 3 and 4 (P=.04 for PTEN and KAI-1, P=.039 for nm23-H1). When all stages were considered together, loss of immunoreactivity for PTEN, nm23-H1 and KAI-1 was found in advanced NCSCLs (P=.015 for PTEN, P=.001 for KAI-1, P=.004 for nm23-H1), which is suggestive of co-downregulation of these proteins in the process of tumor progression. On multivariate analysis, negative staining for PTEN (P=.014), KAI-1 (P=.034), and nm23-H1 (a trend toward association for nm23-H1 reached near significance P=.08) correlated with disease-related death. Positive lymph node status was associated with negative immunostaining for PTEN (P=.007) but no correlation was observed for nm23-H1 and KAI-1. Loss of expression was linked to distant metastasis (P=.006 for PTEN, P=.002 for nm23H1, P=.001 for KAI-1). On multivariate analysis, co-downregulation of PTEN (P=.009), KAI-1 (P=.02), and nm23-H1 (P=.011) independently predicted shortened survival in NSCLC. Although NSCLC exhibits strong co-expression of PTEN, nm23-H1 and KAI-1, there is a loss of these proteins in high-stage tumors. Co-downregulation of PTEN, KAI-1, and nm23-H1 significantly correlates with distant metastasis and predicts shortened survival. Our study supports a role of these tumor suppressor and metastasis suppressor genes in the evolution and progression of NSCLC.
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PMID:Co-downregulation of PTEN, KAI-1, and nm23-H1 tumor/metastasis suppressor proteins in non-small cell lung cancer. 1512 4

Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na+/H+ exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na+/H+ exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in approximately 3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH2-terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.
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PMID:NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. 1546 53


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