Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We analyzed the immunohistochemical expression of the metastasis-associated protein, CD44v3, in 46 primary human malignant melanomas (MMs). This is the first time that the v3 splice variant of CD44 was found to be expressed in human melanomas (15 of 46), ranging from 3% to 35% of the cell population in the positive tumors. The expression of CD44v3 was observed in tumors thicker than 1.0 mm, and one-third of these tumors proved to be positive irrespective of the thickness. Patients were followed for a minimum of 61 months. The onset of lymph node or organ metastases occurred not later than 58 months and 60 months, respectively. Of the 15 CD44v3 positive tumors, 14 were observed in the organ metastatic tumor group, comprising the majority of those cases (14 of 21), and this association proved to be statistically significant compared with the non-metastatic (P<0.05) and lymph-node metastatic cases (P<0.01). CD44v3 expression in melanoma was also confirmed at the protein and messenger (mRNA) level in several human melanoma cell lines using flow cytometry and reverse transcriptase polymerase chain reaction analysis. In parallel to CD44v3, MMP-2 expression (determined using immunohistochemistry) was significantly elevated (P<0.05) but only in the organ metastatic group of MM. The 5-year survival of patients having thicker tumors than 1.0 mm (where v3 expression occurred) who had CD44v3+ tumors was significantly lower than those of the negative ones (35.7% versus 68.2%, respectively; P=0.025). Finally, we observed that the CD44v3-expressing tumors were characterized by significantly higher MMP-2 expression than the CD44v3-negative tumors (P<0.001), indicating a possible correlation between CD44v3- and MMP-2-positive phenotype and the organ metastatic potential of MM.
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PMID:Expression of CD44v3 splice variant is associated with the visceral metastatic phenotype of human melanoma. 1176 82

The expression of metastasis-associated protein 1 (MTA1) correlates well with tumor metastases; however, the associated molecular mechanism is not fully understood. Here, we explored the possibility of cross-talk between MTA1 and hypoxia-inducible factor-1alpha (HIF-1alpha), a key regulator of angiogenic factors. We observed that the expression of MTA1 was strongly induced under hypoxia in breast cancer cell lines such as MCF-7 and MDA-MB-231. When MTA1 was overexpressed, the transcriptional activity and stability of HIF-1alpha protein were enhanced. MTA1 and HIF-1alpha are physically associated in vivo and they were localized completely in the nucleus when coexpressed. MTA1 induced the deacetylation of HIF-1alpha by increasing the expression of histone deacetylase 1 (HDAC1). MTA1 counteracted to the action of acetyltransferase, ARD1, and it did not stabilize the HIF-1alpha mutant that lacks the acetylation site, K532R. These results indicate that acetylation is the major target of MTA1/HDAC1 function. Collectively, our data provide evidence of a positive cross-talk between HIF-1alpha and MTA1, which is mediated by HDAC1 recruitment, and indicate a close connection between MTA1-associated metastasis and HIF-1-induced tumor angiogenesis.
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PMID:Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. 1651 65

Expression of the metastasis-associated protein, ezrin, in over 5,000 human cancers and normal tissues was analyzed using tissue microarray immunohistochemistry. Ezrin staining was compared between cancers and their corresponding normal tissues, between cancers of epithelial and mesenchymal origin, in the context of the putative inhibitor protein, merlin, and against clinicopathological data available for breast, lung, prostate cancers and sarcomas. Ezrin was found in most cancers and normal tissues at varying levels of intensity. In general ezrin was expressed at higher levels in sarcomas than in carcinomas. By normalizing the expression of ezrin in each cancer using ezrin expression found in the corresponding normal tissue, significant associations between ezrin were found in advancing histological grade in sarcomas (P = 0.02) and poor outcome in breast cancer (P = 0.025). Clinicopathologic associations were not changed by simultaneous assessment of ezrin and merlin in each patient sample for the cancer types examined. These data support a role for ezrin in the biology of human cancers and the need for additional studies in breast cancer and sarcoma patients that may validate ezrin as a marker of cancer progression and as a potential target for cancer therapy.
Clin Exp Metastasis 2007
PMID:Expression of the cytoskeleton linker protein ezrin in human cancers. 1737 41

C4.4A is a glycolipid-anchored membrane protein with structural homology to the urokinase-type plasminogen activator receptor (uPAR). Although C4.4A was identified as a metastasis-associated protein little is known about its actual expression and possible function in malignant disease. In the present study, we have therefore analyzed the expression of C4.4A in 14 esophageal squamous cell carcinomas (ESCC). Normal squamous esophageal epithelium shows a strong cell surface associated C4.4A expression in the suprabasal layers, whereas basal cells are negative. Upon transition to dysplasia and carcinoma in situ the expression of C4.4A is abruptly and coordinately weakened. Double immunofluorescence staining of normal and dysplastic tissue showed that C4.4A colocalizes with the epithelial cell surface marker E-cadherin in the suprabasal cells and has a complementary expression pattern compared to the proliferation marker Ki-67. A prominent, but frequently intracellular, C4.4A expression reappeared in tumor cells located at the invasive front and local lymph node metastases. Because C4.4A was reported previously to be a putative laminin-5 (LN5) ligand, and both proteins are expressed by invasive tumor cells, we analyzed the possible coexpression of C4.4A and the gamma 2-chain of LN5 (LN5-gamma 2). Although these proteins are indeed expressed by either neighboring cancer cells or in a few cases even coexpressed by the same cells in the tumor front and metastases, we found no evidence for a general colocalization in the extracellular compartment by confocal microscopy. In conclusion, C4.4A is expressed during invasion and metastasis of human ESCC and may thus provide a new histological marker in this disease.
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PMID:Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma. 1784 75

We evaluated immunohistochemically the expression profiles of metastasis-associated protein (MTA) 1 and their associations with lymph node metastasis in tonsil cancer. Immunohistochemical analysis of 43 tonsillar neoplasm tissues was performed using antibodies raised to MTA1. Depth of tumor invasion, lymph node metastasis, and clinical outcomes were assessed. Clinical N0 patients were divided into two groups: N0a, negative for MTA1; N0b, positive for MTA1. Occult node metastasis was reevaluated according to the revised clinical N staging system taking account of MTA1 expression. The expression rate of MTA1 was 41.9%. There was a significant correlation between the expression of MTA1 and lymph node metastasis (P = 0.034*). MTA1 had a sensitivity of 53.3% and a specificity of 84.6% for identification of cervical metastases. When cN0b patients were considered to be N+, the recalculated rate of occult metastasis fell from 50% to 7.6% (the false-positive rate remained unchanged). MTA1 was found to be a useful molecular marker to predict lymphatic metastasis in tonsil cancer.
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PMID:Relationships between metastasis-associated protein (MTA) 1 and lymphatic metastasis in tonsil cancer. 2124 May 15

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanIN), PDACs, circulating tumor cells, and metastases studied. Confocal microscopy and flow cytometric analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumor cells. Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD. Importantly, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the proinvasive activity of AGR2 included CTSB and CTSD in vitro, and AGR2, CTSB, and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management.
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PMID:AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. 2194 70

We reviewed lymph node samples from 473 consecutive breast cancer cases with either negative sentinel nodes or isolated tumor cells to evaluate the rate of false-positive sentinel node findings. Nuclear morphometry was applied to compare nuclear atypia between the primary tumor and metastases classified as isolated tumor cells by size. In addition, the role of the diagnostic preoperative biopsy method, either core needle biopsy or fine needle aspiration cytology, on the prevalence of isolated tumor cells was investigated. In addition, we studied the expression of metastasis-associated protein 1 in the primary tumor and corresponding metastases in 95 cases, including 52 isolated tumor cell cases, to distinguish a true metastasis from a benign epithelial displacement. Our review revealed 4 false positives and 7 false negatives from 473 sentinel node cases. In addition, 5 true-positive cases were upstaged from isolated tumor cells to micrometastases. No association was found between the preoperative biopsy method and the sentinel node status (P=.859). There was no difference in nuclear atypia, when the cells in isolated tumor cells and primary tumor were compared. Therefore, small metastases do not represent benign epithelial displacement. Isolated tumor cell findings did not correlate with preoperative biopsy methods. The metastasis-associated protein 1 staining score sum was lower in the metastases than in the primary tumor in 72% of cases, including all sizes of metastases. These data suggest that metastasis-associated protein 1 staining is not ideal for investigating the possible malignant nature of smaller metastases because of the relatively low concordance between the primary tumor and metastases, even macrometastases.
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PMID:False-positive and false-negative sentinel node findings in 473 breast cancers. 2257 58

Metastasis is the main cause of cancer-related mortality; patients with liver metastases (LM) have the worst prognosis among patients with nasopharyngeal carcinoma (NPC). However, at present, few biomarkers for detecting organ-specific metastasis have been identified. Proteomics, an ultra-sensitive analytical technique, can detect molecular changes before organ-specific metastasis occurs. Analysis with matrix-assisted, laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS), combined with magnetic chemical affinity beads is a new technique for evaluating protein separation. We sought to identify potential liver-specific, metastasis-associated proteomic printing in patients with NPC. We examined 64 serum samples from 50 patients who had pathologically confirmed NPC and 14 who had pathologically confirmed non-NPC with LM using MALDI-TOF-MS with weak cation bead protein chips. During follow-up of at least 37 months (maximum, 176 months) following radiotherapy, we confirmed 16 cases of LM (LM NPC), 16 cases without LM (non-LM NPC) and 18 cases without metastasis (non-M NPC). Using comparison analysis, 4 protein mass peaks, 4155.34, 4194.87, 4210.78 and 4249.56 m/z were identified as liver-specific, metastasis-associated protein peaks in NPC and two of them (4155 and 4249 m/z) met two different statistical criteria in both ClinProt software analyses and discriminant analyses. Models based on the 4 potential serum markers of NPC discriminated between LM NPC, non-LM NPC, non-M NPC and non-NPC LM analyzed with sieved markers. The recognition capability and cross-validation of these models for differentiating the above 4 groups are all approximately 80%. MALDI-TOF-MS combined with tree analysis models may provide a clinical diagnostic platform for detecting potential liver-specific, metastasis-associated proteomic printing in NPC. However, markedly differential proteins still need to be identified.
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PMID:Comparative serum proteomic analysis involving liver organ-specific metastasis-associated proteins of nasopharyngeal carcinoma. 2297 16

The cause of death for the vast majority of cancer patients is the development of metastases at sites distant from that of the primary tumor. For most pediatric sarcoma patients such as those with osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been seen in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave [1-5]. New treatment options are needed.Opportunities to improve outcomes for patients who present with metastases and those at-risk for progression and metastasis require an improved understanding of cancer progression and metastasis. With this goal in mind we and others have identified ezrin as a metastasis-associated protein that associated with OS and other cancers. Ezrin is the prototypical ERM (Ezrin/Radixin/Moesin) protein family member. ERMs function as linker proteins connecting the actin cytoskeleton and the plasma membrane. Since our initial identification of ezrin in pediatric sarcoma, an increasing understanding the role of ezrin in metastasis has emerged. Briefly, ezrin appears to allow metastatic cells to overcome a number of stresses experienced during the metastatic cascade, most notably the stress experienced as cells interact with the microenvironment of the secondary site. Cells must rapidly adapt to this environment in order to survive. Evidence now suggests a connection between ezrin expression and a variety of mechanisms linked to this important cellular adaptation including the ability of metastatic cells to initiate the translation of new proteins and to allow the efficient generation of ATP through a variety of sources. This understanding of the role of ezrin in the biology of metastasis is now sufficient to consider ezrin as an important therapeutic target in osteosarcoma patients. This chapter reviews our understanding of ezrin and the related ERM proteins in normal tissues and physiology, summarizes the expression of ezrin in human cancers and associations with clinical parameters of disease progression, reviews reports that detail a biological understanding of ezrin's role in metastatic progression, and concludes with a rationale that may be considered to target ezrin and ezrin biology in osteosarcoma.
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PMID:Role of ezrin in osteosarcoma metastasis. 2492 75

The DNA damage, most notably DNA double-strand breaks, poses a serious threat to the stability of mammalian genome. Maintenance of genomic integrity is largely dependent on an efficient, accurate, and timely DNA damage response in the context of chromatin. Consequently, dysregulation of the DNA damage response machinery is fundamentally linked to the genomic instability and a likely predisposition to cancer. In turn, aberrant activation of DNA damage response pathways in human cancers enables tumor cells to survive DNA damages, thus, leading to the development of resistance of tumor cells to DNA damaging radio- and chemotherapies. A substantial body of experimental evidence has established that ATP-dependent chromatin remodeling and histone modifications play a central role in the DNA damage response. As a component of the nucleosome remodeling and histone deacetylase (NuRD) complex that couples both ATP-dependent chromatin remodeling and histone deacetylase activities, the metastasis-associated protein (MTA) family proteins have been recently shown to participate in the DNA damage response beyond its well-established roles in gene transcription. In this thematic review, we will focus on our current understandings of the role of the MTA family proteins in the DNA damage response and their potential implications in DNA damaging anticancer therapy.
Cancer Metastasis Rev 2014 Dec
PMID:MTA family of proteins in DNA damage response: mechanistic insights and potential applications. 2533 44


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