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

In order to determine whether retention or loss of potential tumor suppressor loci that map to 8p, 10q, or 16q reflect genetic relationships among prostatic intraepithelial neoplasias (PINs), multicentric primary prostatic cancers, and regional lymph node metastases or are associated with the metastatic phenotype, we analyzed 19 cases of locally metastatic prostate carcinoma (stage D1) utilizing polymerase chain reaction techniques. In each case, tissue samples from metastatic tumor, the (dominant) primary tumor, and nonneoplastic prostatic tissue were examined. In selected cases, allelic loss in additional tumor foci, separate from the dominant tumor nodule, and areas of PIN were examined. Allelic loss of sequences on 8p, 10q, and 16q were observed in 20-29% of PINs, 18-42% of primary tumors, and 8-25% of metastatic tumors. Discrepancies in sequence dosage between histological components were most pronounced for 8p sequences, especially between the dominant tumor nodule and metastatic deposits in cases in which > or = 3 separate tumor foci/gland were identified. These results suggest that putative premalignant lesions, moderately or poorly differentiated, geographically separate primary tumor foci, and metastases within morphologically "complex" prostates (those with > or = 3 foci/gland) are likely to be more discordant for sequence dosage at 8p than those within "simpler" glands (< 3 foci/gland). Also, our results suggest that lymph node metastases may be genetically related to either the dominant or additional primary tumor foci in more complex prostates and that accumulation of genetic aberration may differ in primary and metastatic lesions.
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PMID:Allelic loss in locally metastatic, multisampled prostate cancer. 751 68

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors), 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup, 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%), P = 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension, the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases.
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PMID:Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases. 973 17

APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.
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PMID:Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. 1537 5

The TGF-beta superfamily is the most versatile considering the ability of its members to regulate proliferation, growth arrest, differentiation, and apoptosis of prostatic stromal and epithelial cells as well as the formation of osteoblastic metastases. TGF-beta mediated action in prostate cells follows a complex signaling pathway from binding and phosphorylation of receptor type II to the TbetaRI kinase to Smad activation, resulting in ligand-induced transcription. TGF-beta as an indirect tumor suppressor, its role of regulating tumor induction, as well as tumor suppression depending on the tissue microenvironment merits further exploration. The rationale for targeting growth factors and their receptors for therapeutic intervention is based upon the fact that these proteins represent the most proximate component of the signal transduction cascade. The alternate targeting of intracellular effectors in the signal transduction may be thwarted by cross talk between signaling pathways (such as the Smads in a dynamic interplay with the androgen receptor). TGF-beta within the context of its well-documented apoptosis regulatory actions in the prostate and the significance its key receptor TbetaRII as a potential tumor suppressor, provides a highly attractive candidate for such targeting with high clinical significance for the treatment and diagnosis of prostate cancer.
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PMID:Transforming growth factor beta and prostate cancer. 1620 66

Deletions on the long arm of chromosome 15 suggesting the presence of potential tumor suppressor genes have been found in several tumors including carcinomas of the colorectum, urinary bladder, breast, lung, and head and neck. Here, we analyzed allelic imbalance on chromosome 15q in head and neck carcinomas and corresponding lymph node metastases to define common regions of aberrations with potential involvement in development and progression of these tumors. We studied a panel of 40 polymorphic microsatellite markers, spanning 15q13-15q26, in 63 head and neck carcinomas and 38 lymph node metastases. Loss of heterozygosity (LOH) could be demonstrated in 34 primary tumors (54%) and 35 metastases (92%). Aberration mapping defined three minimum regions of aberrations: a region between the markers D15S106 and D15S1029 in 15q21.3 (estimated as 3.9 Mb; region 1) was affected in the majority of tumors, whereas two other regions between D15S144 and D15S1040 in 15q13.3-14 (estimated as 2.4 Mb; region 2) and between D15S130 and D15S985 in 15q26.2-26.3 (estimated as 4.7 Mb; region 3) were less often involved. Allelic loss in region 1 correlated with T stages (P=0.0029) and metastatic potential (P=0.0018). LOH in regions 2 and 3 occurred predominantly in metastases (P=0.0129 and P=0.0013, respectively). No correlation with grading, localization, or clinical outcome could be established for any of the affected regions. Our data hint at aberrations in 15q21.3 as a possible important characteristic for head and neck squamous cell carcinomas with risk of progression.
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PMID:Loss of heterozygosity at 15q21.3 correlates with occurrence of metastases in head and neck cancer. 1690 32

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myelogenous leukemia. Remarkably, drugs such as forskolin, 1,9-dideoxy-forskolin and FTY720 which lead to PP2A activation effectively antagonize leukemogenesis in both in vitro and in vivo models of these cancers. Thus, PP2A is now in the spotlight as a highly promising drugable target for the development of a new series of anticancer agents potentially capable of overcoming drug-resistance induced in patients by continuous exposure to kinase inhibitor monotherapy. Herein, we review current knowledge of PP2A biology and function with particular emphasis on its tumor suppressor activity and possible therapeutic implications in cancer.
Cancer Metastasis Rev 2008 Jun
PMID:Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. 1821 49

Diverse cellular processes are regulated by tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). De-regulated tyrosyl phosphorylation, evoked by gain-of-function mutations and/or over-expression of PTKs, contributes to the pathogenesis of many cancers and other human diseases. PTPs, because they oppose the action of PTKs, had been considered to be prime suspects for potential tumor suppressor genes. Surprisingly, few, if any, tumor suppressor PTPs have been identified. However, the Src homology-2 domain-containing phosphatase Shp2 (encoded by PTPN11) is a bona fide proto-oncogene. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, whereas somatic PTPN11 mutations occur in several types of hematologic malignancies, most notably juvenile myelomonocytic leukemia and, more rarely, in solid tumors. Shp2 also is an essential component in several other oncogene signaling pathways. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into oncogenic mechanisms and novel targets for anti-cancer therapy.
Cancer Metastasis Rev 2008 Jun
PMID:The tyrosine phosphatase Shp2 (PTPN11) in cancer. 1828 34

DLC-1 was originally identified as a potential tumor suppressor. One of the key biochemical functions of DLC-1 is to serve as a GTPase activating protein (GAP) for members of the Rho family of GTPases, particularly Rho A-C and Cdc 42. Since these GTPases are critically involved in regulation of the cytoskeleton and cell migration, it seems clear that DLC-1 will also influence these processes. In this review we examine basic aspects of the actin cyoskeleton and how it relates to cell motility. We then delineate the characteristics of DLC-1 and other members of its family, and describe how they may have multiple effects on the regulation of cell polarity, actin organization, and cell migration.
Cancer Metastasis Rev 2009 Jun
PMID:Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. 1922 66

The diagnosis of a malignant pheochromocytoma (PC) can only be established by the presence of distant metastases, but a subset of apparently benign PCs develop metastases. We have employed a microarray analysis to identify a typical gene expression profile which distinguishes malignant from benign PC. Total RNA was isolated from fresh-frozen tissue of five benign and five malignant PCs. The reference consisted of laser microdissected tissue from normal adrenal medulla. After generating Cy3- and Cy5-fluorescently labeled cDNAs, F-chips containing 11 540 spots were hybridized. Data were analyzed with the IMAGENE 3.0 software. Gene expression levels were validated by real-time (RT)-PCR and immunohistochemistry (IHC). The analysis revealed a more than twofold difference in expression between benign and malignant PCs in 132 genes: 19 were up-regulated and 113 were down-regulated. Expression differences of six genes (calsequestrin, NNAT, neurogranin, secreted protein acidic and rich in cysteine (SPARC), EGR2, and MAOB) were confirmed by RT-PCR in 25 PCs. IHC for calsequestrin revealed an overexpression in malignant PCs (7/10 vs 1/10, P=0.03). Comparative analysis by microarray of all ten PCs (benign/malignant) versus normal adrenal medulla revealed a more than twofold expression difference in 455/539 and 491/671 genes respectively. Several of these genes are known to participate on adrenal tumorigenesis, potential tumor suppressor genes, and oncogenes. Comprehensive gene expression analysis of malignant and benign PCs revealed different gene profiles, which could be used to discriminate between malignant and benign PCs. Based on these findings, the strategy for further follow-up and treatment could be modified accordingly.
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PMID:Microarray analysis reveals differential expression of benign and malignant pheochromocytoma. 2056 31

Glioblastomas (GBMs) are the highest grade of primary brain tumors with astrocytic similarity and are characterized dispersal of tumor cell. Metastasis suppressor 1 (MTSS1) play an important role in cancer metastasis. Recent studies indicating that MTSS1 as a potential tumor suppressor and its reduced expression associated with poor prognosis in many cancer types. However, the relationship with the prognosis of patients and the molecular mechanism of MTSS1 renders a tumor suppressor effect in GBM is unknown. Here, we showed that low MTSS1 gene expression is associated with poor outcomes in patients with GBM. Overexpression of MTSS1 in U-87 MG cells exhibited inhibited glioma cell growth, colony formation, migration and invasion. Mechanistically, we found that high MTSS1 expression in U-87 MG reduced expression of CTTN. These results implicate that the role of MTSS1 suppresses cell migration and invasion by inhibiting expression of CTTN and as a prognosis biomarker in GBM.
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PMID:MTSS1 suppresses cell migration and invasion by targeting CTTN in glioblastoma. 2538 72


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