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)

The Wild-type p53-induced phosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cdelta), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16(INK4a) and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.
Cancer Metastasis Rev 2008 Jun
PMID:The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. 1826 45

Recent evidence demonstrates that senescence acts as a barrier to tumorigenesis in response to oncogene activation. Using a mouse model of breast cancer, we tested the importance of the senescence response in solid cancer and identified genetic pathways regulating this response. Mammary expression of activated Ras led to the formation of senescent cellular foci in a majority of mice. Deletion of the p19(ARF), p53, or p21(WAF1) tumor suppressors but not p16(INK4a) prevented senescence and permitted tumorigenesis. Id1 has been implicated in the control of senescence in vitro, and elevated expression of Id1 is found in a number of solid cancers, so we tested whether overexpression of Id1 regulates senescence in vivo. Although overexpression of Id1 in the mammary epithelium was not sufficient for tumorigenesis, mice with expression of both Id1 and activated Ras developed metastatic cancer. These tumors expressed high levels of p19(Arf), p53, and p21(Waf1), demonstrating that Id1 acts to make cells refractory to p21(Waf1)-dependent cell cycle arrest. Inactivation of the conditional Id1 allele in established tumors led to widespread senescence within 10 days, tumor growth arrest, and tumor regression in 40% of mice. Mice in which Id1 expression was inactivated also exhibited greatly reduced pulmonary metastatic load. These data demonstrate that established tumors remain sensitive to senescence and that Id1 may be a valuable target for therapy.
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PMID:Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. 1837 7

Functional inactivation of the tumour suppressor protein p16(INK4a) constitutes a key event in the multistep process of pancreatic ductal cell transformation. However, the significance of p16 inactivation for complex and tissue-specific aspects of pancreatic cancer progression, such as angiogenesis and metastasis, is less understood. Here, we inducibly re-expressed p16 in vivo in an orthotopic model of pancreatic cancer and examined the impact on these clinically relevant aspects of pancreatic cancer tumour biology. Consistent with previous work in subcutaneous xenograft models, we found p16 capable of reducing primary tumour growth. In addition, p16 restitution resulted in a marked reduction of tumour angiogenesis, largely accounted for by a p16-dependent inhibition of lymphangiogenesis. In excellent agreement with the antilymphangiogenic effect, re-expression of p16 almost completely prevented lymph node metastases of MiaPaca-2 pancreatic tumours. To our knowledge, this is the first report that experimentally links the tumour suppressor p16 to the process of lymphangiogenesis.
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PMID:Inducible re-expression of p16 in an orthotopic mouse model of pancreatic cancer inhibits lymphangiogenesis and lymphatic metastasis. 1857 84

Cutaneous melanoma is one of the leading causes of cancer-related death. Malignant transformation of epidermal melanocytes is a multifactorial process involving cell cycle and death control pathways. The purpose of this study was to analyze the immunohistochemical expression of cell-cycle-related and apoptosis-related proteins in cutaneous superficial spreading melanomas using the tissue microarray technique to further understand tumor development. A total of 20 samples of in-situ melanomas and 44 melanomas <or=1.0 mm were analyzed in conventional sections whereas 72 melanomas greater than 1.0 mm and 29 metastases were evaluated by tissue microarray. The sections were stained for the following proteins: p16INK4 (p16), cyclin D1, cyclin-dependent kinase 4 (Cdk4), retinoblastoma protein, tumor suppressor protein p53, and p21 cell cycle regulator (p21) using a streptavidine-biotin-peroxidase technique for immunohistochemistry. Thick melanomas (>1.0 mm) and metastases lost p16 expression in 100% of the cases and in-situ and thin melanomas (<or=1.0 mm) had low rate of p16 expression (7.9%). When comparing thin versus thick melanomas, thin melanomas showed higher expression of cyclin D1 and cytoplasmatic Cdk4, and thick melanomas had increased expression of nuclear Cdk4, tumor suppressor protein p53, and p21. Primary tumors, when compared with metastases, had higher cytoplasmatic Cdk4 expression. None of the studied proteins influenced overall or disease-free survival. Our results suggest that loss of p16 expression was a constant feature in primary and metastatic melanomas. Cyclin D1 expression seems to be related to initial phases of melanoma development. An increase in p21 expression could represent a cell cycle control in proliferating cells with reduced p16 and/or increased nuclear Cdk4 expression.
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PMID:Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas. 1936 1

Genetic alterations in metastatic cutaneous squamous cell carcinoma (CSCC) which might serve as prognostic biomarkers are not well investigated. We investigated the mutation status and protein expression of the CDKN2A (INK4a-ARF) and TP53 genes in metastatic CSCCs and correlated this with clinicopathological variables, HPV presence, and survival data. Sequence analysis was performed on formalin-fixed and paraffin-embedded tissue of 35 metastases and their primary tumors, and was correlated with immunohistochemical stainings for p53, p16 and p14. Beta-PV and alpha-PV DNA was detected using PCR-based assays. Kaplan-Meier and Cox regression methods were used for survival assessment. CDKN2A was mutated in 31% of the metastases and their primary tumors, while the TP53 gene was mutated in 51% of the metastases. P53 protein expression was significantly associated with missense type of mutations (p = 0.002). No persistent HPV types were detected. CDKN2A mutations were significantly associated with disease-specific death (p = 0.001). A significant difference was observed in disease-specific survival between patients with or without a CDKN2A mutation (p = 0.010), while this was not the case for TP53. At univariate Cox's regression analysis tumor size (p = 0.010), invasion depth (p = 0.030) and CDKN2A mutations (p = 0.040) were significantly related to shorter disease-specific survival. At multivariate Cox's regression only tumor size had an adverse effect on survival (p = 0.002). In conclusion, our study indicates that the CDKN2A mutation status might be of prognostic value in metastatic CSCCs. In most cases, CDKN2A and TP53 mutations are early genetic events in CSCC tumorigenesis. The possible role of HPV in metastatic CSCC needs further exploration.
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PMID:CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin. 1973 23

Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2, and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging. Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2-invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies.
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PMID:The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis. 2163 82

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors with a high rate of local recurrence and a significant tendency to metastasize. Its dismal outcome points to the urgent need to establish better therapeutic strategies for patients harboring MPNSTs. The investigations of genomic and molecular aberrations in MPNSTs which detect many chromosomal aberrations, pathway abnormalities, and specific molecular aberrant events would supply multiple potential therapy targets and contribute to achievement of personalized medicine. The involved genes in the significant gains aberrations include BIRC5, CCNE2, DAB2, DDX15, EGFR, DAB2, MSH2, CDK6, HGF, ITGB4, KCNK12, LAMA3, LOXL2, MET, and PDGFRA. The involved genes in the significant deletion aberrations include CDH1, GLTSCR2, EGR1, CTSB, GATA3, SULT2A1, GLTSCR2, HMMR/RHAMM, LICAM2, MMP13, p16/INK4a, RASSF2, NM-23H1, and TP53. These genetic aberrations involve in several important signaling pathways such as TFF, EGFR, ARF, IGF1R signaling pathways. The genomic and molecular aberrations of EGFR, IGF1R, SOX9, EYA4, TOP2A, ETV4, and BIRC5 exhibit great promise as personalized therapeutic targets for MPNST patients.
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PMID:Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy. 2383 Mar 51

Osteosarcoma (OS) is the eighth most common form of childhood and adolescence cancer. Approximately 10%-20% of patients present metastatic disease at diagnosis and the 5-year overall survival remains around 70% for nonmetastatic patients and around 30% for metastatic patients. Metastatic disease at diagnosis and the necrosis grade induced by preoperative treatment are the only well-established prognostic factors for osteosarcoma. The DNA aberrant methylation is a frequent epigenetic alteration in humans and has been described as a molecular marker in different tumor types. This study evaluated the DNA aberrant methylation status of 18 genes in 34 OS samples without previous chemotherapy treatment and in four normal bone specimens and compared the methylation profile with clinicopathological characteristics of the patients. We were able to define a three-gene panel (AIM1, p14ARF, and ESR1) in which methylation was correlated with OS cases. The hypermethylation of p14ARF showed a significant association with the absence of metastases at diagnoses, while ESR1 hypermethylation was marginally associated with worse overall survival. This study demonstrated that aberrant promoter methylation is a common event in OS and provides evidence that p14ARF and ESR1 hypermethylation could be useful as a prognostic indicator for this disease.
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PMID:Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma. 2383 83

Although rare, congenital malignant melanoma (CMM) should be considered in the differential diagnosis of congenital skin lesions. We report a case of CMM in a 4-month-old infant presenting with an enlarging scalp mass, initially thought to be a hemangioma. Incisional biopsy of the lesion showed a compound congenital nevus with atypical cells suggestive of a proliferative nodule versus malignancy on histopathology. Subsequent excisional biopsy revealed malignant melanoma, and further workup confirmed extensive disease with distant metastases. Cytogenetic analysis of both the tumor sites showed highly abnormal karyotypes including pseudotetraploidy, telomere associations, and evidence of gene amplification, all consistent with malignancy. Fluorescence in situ hybridization demonstrated amplification of the MYC gene, with no copy number changes in CDKN2A (INK4/ARF), PTEN, or Cyclin D1. Our report details the cytogenetic and molecular studies of CMM, which provide insight into the biologic behavior of the lesions and may confirm diagnosis when histopathology is not determinant.
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PMID:Congenital malignant melanoma: a case report with cytogenetic studies. 2390 18

We report a very rare case of a dedifferentiated chondrosarcoma mimicking a benign giant cell tumor. A 22-year-old male was admitted to our hospital with a history of mild left wrist pain after a skiing trauma. Radiology revealed an extensive meta-epiphyseal osteolytic lesion in the distal ulna, which appeared to be a giant cell tumor. Histological examination showed a biphasic tumor comprising chondroid and non-chondroid areas with a giant cell-rich lesion resembling a conventional giant cell tumor of the bone. Immunohistochemistry showed no expression of p16(INK4a), VEGFR1, KDR (VEGFR2), VEGFR3, cKIT, MDM2 or CDK4. However, high expression of the tyrosine kinases PDGFRA and PDGFRB was observed. Molecular analysis showed no amplification of the cMYC gene and no activating mutations in the cKIT (exons 9 and 11) or PDGFRA (exon 18) genes. He has been on follow-up for ten months, with no evidence of local recurrence or metastatic disease. In summary, this report highlights a very rare case of a dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor bears histologic resemblance to a conventional giant cell tumor of bone. We suggest that this tumor might be categorized in the group of low-grade dedifferentiated chondrosarcomas.
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PMID:Dedifferentiated chondrosarcoma mimicking a giant cell tumor. Is this low grade dedifferentiated chondrosarcoma? 2440 42


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