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)

To understand immune responses to human cancer and develop more effective immunotherapy, human tumor antigens has been isolated using various immunological methods with tumor reactive T cells or antibodies obtained from patients with melanoma. During the process of tumor antigen isolation, various molecules with genetic alterations or over-expression in tumor cells, which may be involved in proliferation, differentiation, or survival of various cancer cells, were identified. In melanoma, abnormal molecules with mutations including beta -catenin, CDK4, and BRAF, and molecules with increased expression including Survivin, were immunologically detected. Therefore, immunological isolation of human tumor antigens contributes to the identification of important molecules including altered signaling molecules involved in melanoma formation.
Cancer Metastasis Rev 2005 Jun
PMID:Immunological detection of altered signaling molecules involved in melanoma development. 1598 43

Currently, novel mouse models of melanoma are being generated that recapitulate the histopathology and molecular pathogenesis observed in human disease. Impaired cell-cycle control, which is a hallmark of both familial and sporadic melanoma, promotes slowly growing carcinogen-induced melanomas in the skin of mice carrying a mutated cyclin-dependent kinase 4 (CDK4(R24C)). Deregulated receptor tyrosine kinase signaling, which is another important feature of human melanoma, leads to spontaneous development of metastatic melanoma after a long latency period in mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF mice). Here we report that treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate induced metastatic melanomas in all HGF/SF mice on the C57BL/6 background, which histologically resemble human melanoma. Importantly, mutant CDK4 dramatically increased the number and the growth kinetics of carcinogen-induced primary melanomas in the skin and promoted the growth of spontaneous metastases in lymph nodes and lungs in all HGF/SF mice within the first 3 months of life. Apart from very few skin papillomas, we did not observe tumors of other histology in carcinogen-treated HGF/SF x CDK4(R24C) mice. This new experimental mouse model can now be exploited to study further the biology of melanoma and evaluate new treatment modalities.
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PMID:Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. 1687 64

Melanoma is the most dangerous of all common skin cancers, due to its propensity to metastasize. Therefore, identification of at-risk populations may allow early detection of disease at a curable stage. In Europe and North America, between 8-14% of melanoma patients have a family history of the disease, and a subset of these individuals possess germline mutations in the CDKN2A gene, which encodes the p16(INK4A) and p14(ARF) tumor suppressors. We identified 30 patients (29 families) from Southern Brazil, who had a family history of melanoma and/or pancreatic cancer; or a personal history of multiple primary melanoma. We screened this cohort for mutations in the CDKN2A and CDK4 genes, and detected two functional mutations: a G-34T transversion in 5'untranslated region; and a M53I alteration encoded in exon 2. Both mutants have been previously associated with melanoma and demonstrate founder effects. We conclude that germline mutations of CDKN2A occur in the Brazilian population, and that these mutations likely originated in Europe.
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PMID:Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil. 1771 69

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
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PMID:The genome and epigenome of malignant melanoma. 1804 49

Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c-MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c-MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high-grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high-grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high-grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high-grade chondrosarcoma.
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PMID:Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. 1862 51

Transforming growth factor (TGF)-beta initially inhibits growth of mature epithelial cells. Later, however, autocrine TGF-beta signaling acts in concert with the Ras pathway to induce a proliferative and invasive phenotype. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also Ras-associated kinases, which differentially phosphorylate the mediators Smad2 and Smad3 to create distinct phosphorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C) and both linker and COOH-terminally phosphorylated Smad2/3 (pSmad2L/C and pSmad3L/C). In this study, we investigated actions of pSmad2L/C and pSmad3L/C in cancer progression. TGF-beta inhibited cell growth by down-regulating c-Myc oncoprotein through the pSmad2C and pSmad3C pathway; TGF-beta signaling, in turn, enhanced cell growth by up-regulating c-Myc through the cyclin-dependent kinase (CDK) 4-dependent pSmad2L/C and pSmad3L/C pathways in cell nuclei. Alternatively, TbetaRI and c-Jun NH2-terminal kinase (JNK) together created cytoplasmic pSmad2L/C, which entered the nucleus and stimulated cell invasion, partly by up-regulating matrix metalloproteinase-9. In 20 clinical samples, pSmad2L/C and pSmad3L/C showed nuclear localization at invasion fronts of all TGF-beta-producing human metastatic colorectal cancers. In vitro kinase assay confirmed that nuclear CDK4 and cytoplasmic JNK obtained from the tumor tissue could phosphorylate Smad2 or Smad3 at their linker regions. We suggest that CDK4, together with JNK, alters tumor-suppressive TGF-beta signaling to malignant characteristics in later stages of human colorectal cancer. The linker phosphorylation of Smad2 and Smad3 may represent a target for intervention in human metastatic cancer.
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PMID:Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer. 1953 54

Dedifferentiated liposarcoma (LPS) is a malignant adipocytic neoplasm defined as the transition from well-differentiated LPS to a nonlipogenic sarcoma. Heterologous differentiation is seen in 5% to 10% of dedifferentiated LPS, usually with myogenic or osteo/chondrosarcomatous elements. Adipocytic differentiation in the dedifferentiated component is incompatible with the current definition of dedifferentiated LPS. Pleomorphic LPS is a high-grade sarcoma containing lipoblasts. At least in areas, pleomorphic LPS can be indistinguishable from dedifferentiated LPS, except for the presence of lipoblasts in pleomorphic LPS and well-differentiated LPS areas in dedifferentiated LPS. We evaluated 12 unusual liposarcomas: 11 cases with pleomorphic LPS-like morphology affecting patients with concomitant or previous well-differentiated/dedifferentiated LPS, and 1 case resembling inflammatory "MFH" with scattered lipoblasts. Clinical and histologic features were reviewed. Immunohistochemistry for MDM2 and CDK4 was carried out. Amplification of 12q13 to q15 was studied by FISH analysis of the HMGA2 locus. The tumors arose in the retroperitoneum (7), proximal lower extremity (3), chest wall (1), and neck (1) of 9 males and 3 females (median age 66 y; range 49 to 76). Size ranged from 9 to 32 cm (median 23 cm). In 3 cases, there was an abrupt transition between well-differentiated LPS and sheets of pleomorphic lipoblasts, indistinguishable from pleomorphic LPS. Four cases consisted of otherwise typical dedifferentiated LPS (with adjacent well-differentiated LPS), except for the presence of lipoblasts in the high-grade component. One case contained both nonlipogenic spindle cell areas and an inflammatory "MFH"-like component with numerous admixed lipoblasts. Four cases were composed exclusively of pleomorphic LPS-like areas developing in 1 of the recurrences or metastases of a prior typical dedifferentiated LPS. Two cases also showed heterologous smooth muscle differentiation. MDM2 and CDK4 were positive in both the dedifferentiated LPS and pleomorphic LPS-like components in 12/12 and 11/12 cases, respectively. FISH analysis showed high-level amplification of 12q14.3 in all 8 cases successfully tested. Karyotypes were available for 3 cases and showed ring and giant marker chromosomes. Follow-up, available for 11 patients, ranged from 19 to 196 months (median 36 mo). Seven patients developed local recurrences (multiple in 3), and 3 developed lung metastases. Thus far, 5 patients have died of disease, 3 are alive with recurrent or metastatic disease, and 3 are alive with no evidence of disease. We conclude that dedifferentiated LPS can show lipoblastic differentiation in the high-grade component, resulting in areas indistinguishable from pleomorphic LPS. The available clinical and molecular data support the notion of "homologous" lipoblastic differentiation in dedifferentiated LPS, rather than mixed-type LPS.
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PMID:Dedifferentiated liposarcoma with "homologous" lipoblastic (pleomorphic liposarcoma-like) differentiation: clinicopathologic and molecular analysis of a series suggesting revised diagnostic criteria. 2058 77

Sarcomatous transformation of chromophobe renal cell carcinoma (CRCC) is a well recognized phenomenon. Of the published cases with sarcomatous transformation of CRCC, none have shown liposarcomatous differentiation. Out of a cohort of 250 cases of CRCC, 19 (7.6%) showed sarcomatous differentiation. In one case (female, age 46 years), the sarcomatous component of the tumor displayed histological features of a pleomorphic liposar-coma. Light microscopic examination revealed a biphasic pattern with a chromophobe renal cell carcinoma(CRCC) and a high-grade sarcomatous component containing large pleomorphic lipoblasts. In several areas both components were intermingled. The conventional CRCC component showed classic histological features with calcifications, medium-sized polygonal cells arranged in solid-alveolar structures with raisinoid nuclei, pale-eosinophilic flocculent cytoplasm with perinuclear haloes. In addition, a microcystic-adenomatous component had luminal spaces filled with erythrocytes. The CRCC was positive with Hale's colloidal iron-stain whereas the sarcomatous component was negative. The CRCC component was diffusely positive for cytokeratin 7, parvalbumin and racemase but negative for cy-tokeratin 20, vimentin, CD10, carboanhydrase IX and S100-protein. The pleomorphic liposarcomatous component displayed immunereactivity for CD10, vimentin, racemase and focally for carboanhydrase IX. The proliferative activity (Mib-1/Ki-67) was 5% in the CRCC and 30% in the pleomorphic liposarcomatous component. No immunereactivity for MDM2 or CDK4 was detected.This is the first reported case of a sarcomatoid CRCC where the sarcomatous component displayed features of a pleomorphic liposarcoma. The patient died from widespread metastatic disease 12 months after nephrectomy.
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PMID:Chromophobe renal cell carcinoma with liposarcomatous dedifferentiation - report of a unique case. 2083 Feb 47

Mature bone formation in well-differentiated liposarcoma and dedifferentiated liposarcoma has been described as a reactive or "metaplastic" change in most reports, and its neoplastic nature has not been widely appreciated. We herein describe 9 cases of well-differentiated/dedifferentiated liposarcoma with distinct areas of fibroosseous tissue histologically indistinguishable from low-grade osteosarcomas, that is, parosteal osteosarcoma or low-grade central osteosarcoma. The tumors affected middle-aged to elderly patients, and occurred in the retroperitoneum and deep soft tissue of the extremities without connection to the skeletal system. Grossly, all the tumors showed biphasic appearance with lipogenic and osteogenic area, the latter representing 5% to 50% of the total tumor volume. Histologically, the lipogenic component exhibited typical histology of well-differentiated liposarcoma, whereas the osteogenic area consisted of fibroosseous tissue with numerous mature neoplastic bone trabeculae largely lacking osteoblastic rimming, with intervening fascicles of spindle cell proliferation showing low nuclear grade. All samples were positive for MDM2 and/or CDK4 on immunohistochemical analysis; the antibodies stained many osteocytes, indicating that the bone is neoplastic rather than reactive. Three cases showed high-grade osteosarcomatous transformation juxtaposed to the low-grade osteosarcomatous component, reminiscent of the "dedifferentiation" phenomenon of skeletal low-grade osteosarcoma. Follow-up revealed local recurrence in 4 cases, but no distant metastases were documented. Recognition of this earlier underappreciated subtype of well-differentiated/dedifferentiated liposarcoma is important, because the fibroosseous component may seem so bland that it may be confused with benign metaplasia such as myositis ossificans, or conversely, the lipomatous component may be inconspicuous that it may be dismissed as normal fat, and such misinterpretation may potentially result in suboptimal treatment.
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PMID:Well-differentiated liposarcoma with low-grade osteosarcomatous component: an underrecognized variant. 2069 54

Several microRNAs (miRNA) have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer that is widely prevalent in southern China. In this study, we report that microRNA miR-26a is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. Ectopic expression of miR-26a dramatically suppressed cell proliferation and colony formation by inducing G(1)-phase cell-cycle arrest. We found that miR-26a strongly reduced the expression of EZH2 oncogene in NPC cells. Similar to the restoring miR-26 expression, EZH2 downregulation inhibited cell growth and cell-cycle progression, whereas EZH2 overexpression rescued the suppressive effect of miR-26a. Mechanistic investigations revealed that miR-26a suppressed the expression of c-myc, the cyclin D3 and E2, and the cyclin-dependent kinase CDK4 and CDK6 while enhancing the expression of CDK inhibitors p14(ARF) and p21(CIP1) in an EZH2-dependent manner. Interestingly, cyclin D2 was regulated by miR-26a but not by EZH2, revealing cyclin D2 as another direct yet mechanistically distinct target of miR-26a. In clinical specimens, EZH2 was widely overexpressed and its mRNA levels were inversely correlated with miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth-suppressive miRNA in NPC, and that its suppressive effects are mediated chiefly by repressing EZH2 expression.
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PMID:MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. 2119 4


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