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)

The histogenesis of malignant melanoma with particular reference to the role of melanocytic nevus is still controversial in oncological pathology. In order to differentiate between the proliferative activity of malignant melanomas and benign melanocytic tumors, immunohistochemical analysis was carried out. We used monoclonal antibody PC10 to identify the Proliferating Cell Nuclear Antigen (PCNA), a highly conserved 36 KD acidic nuclear protein which correlates with cell proliferation, and the AgNOR method to stain the Nucleolar Organizer Regions (NORs) whose number and configurations may reflect protein synthesis activity. 47 cases of primary melanoma, 63 metastatic melanoma lesions, and 23 cases of nevi are included in this study. Spitz nevi showed a higher index of cell proliferation compared with other common benign nevi but a much lower index compared with malignant melanoma cells. The metastatic lesions of malignant melanomas had a higher index of proliferation and activity of cells than the primary lesions. Skin-metastatic lesions had higher indexes of cell proliferation and NOR activity than lymph node-metastatic lesions. These results support the idea that metastatic melanoma cells are derived from a more advanced stage of tumor progression. These data suggest that the combination of PCNA and AgNOR is an useful marker for differentiating benign melanocytic tumors from malignant melanomas.
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PMID:PCNA expression and nucleolar organizer regions in malignant melanoma and nevus cell nevus. 773

N-myc oncogene amplification in neuroblastoma has been found to be significantly associated with advanced stage disease and tumor progression. However, there is a lack of data on tumors, regarding the relationship between N-myc gene amplification and proliferation activity. Proliferating cell nuclear antigen (PCNA) is a proliferation-induced 36 kD nuclear protein that is the auxiliary component of DNA polymerase delta. PCNA levels in tissues have been found to correlate with proliferative activity. We have examined PCNA levels in neuroblastomas in relation to N-myc gene amplification and tumor stage. Statistically, significantly higher levels of PCNA were observed in tumors with an amplified N-myc gene relative to tumors with a single gene copy. The highest levels of PCNA were observed in advanced stage tumors with an amplified N-myc gene. Treatment of neuroblastoma cells in culture with retinoic acid, which induces differentiation, resulted in a substantial decrease in PCNA. Our results suggest that PCNA levels may reflect differences in proliferative activity between neuroblastomas, related to stage of the disease and to N-myc gene copy number.
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PMID:PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors. 809 85

The wild-type tumor-suppressor TP53 gene encodes for a nuclear protein which has been shown to act as a transcriptional modulator. The cellular role of the p53 protein is the control of cell proliferation, particularly important in stressed cells. The TP53 gene is frequently mutated in sporadic and familial human cancers. Most transforming mutations localize in highly conserved domains of the gene and define hot-spot regions that have a certain degree of tissue specificity. Moreover, most mutations are point mutations and the type and localization of the nucleotide substitution may sometimes help in recognizing the carcinogenic agent. This is the case for C to T transitions at dipyrimidine sites induced by UV radiation in cutaneous epitheliomas. Inactivation of p53 protein can also occur through mechanisms other than genetic alteration, such as binding to viral or cellular proteins. Loss of wild-type TP53 function seems therefore to play a crucial role in cell transformation in human cancers, either during carcinogenesis or later in tumor progression.
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PMID:TP53 tumor-suppressor gene and human carcinogenesis. 816 31

In 68 cases of surgically resected gastric carcinomas, expression of human epidermal growth factor (EGF) and its receptor (EGFR) were examined immunohistologically using the Avidin-Biotin Peroxidase Complex Method, and their relation with DNA contents and nuclear protein synthesis in the tumor progression were studied by measuring DNA ploidy patterns and nucleolar organizer regions (NORs), respectively with cytofluorometry and AgNO3 stain method. EGF and EGFR expression were respectively found only in 2 (7%) and 1 (4%) in 28 early cancers, and significantly increased in advanced cancers, 25 (63%) and 9 (23%) out of 40 cases. The ratio of aneuploid tumor and the NORs numbers per tumor cell also increased in advanced cancers, compared with in early cancers. EGF and EGFR respectively expressed in 19 (51%) and 9 (23%) in 37 aneuploid cancers, significantly more frequent than 8 (26%) and 1 (3%) in 31 diploid cancers. In the EGF-positive tumors, the NORs numbers showed 4.11 +/- 0.72, significantly higher than 2.68 +/- 0.61 in the EGF-negative tumors. These results suggested that expression of EGF and EGFR in the gastric carcinomas increases during the tumor progression from the early to advanced stage, stimulates synthesis of DNA and nuclear protein, and consequently enhances (strengthens, heightens, or intensifies) the proliferative activity of the tumors.
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PMID:[Expression of human epidermal growth factor and its receptor of the gastric carcinomas with special reference to DNA ploidy patterns and nucleolar organizer regions]. 817 99

The optimal clinical management of minimally invasive (stage T1) bladder cancer is controversial. T1 bladder cancers share characteristics of both noninvasive (Ta) papillary cancer and high stage, muscle-invasive bladder cancers. Patients with T1 bladder cancer have a higher risk of cancer progression and death than do patients with Ta bladder cancer. However, this risk is much lower than that of patients with high-stage bladder cancers. Methods of identifying T1 bladder cancer patients at greatest risk for progression may significantly improve clinical management. We retrospectively evaluated two tumor suppressor genes, p53 and RB, as potential prognostic markers for progression in a cohort of 45 patients with pT1 bladder cancer. Median follow-up for these individuals was greater than 3.5 years. Of this group, 58% had altered p53 expression based on positive p53 immunostaining. Three patterns for RB nuclear protein staining were observed: absent, heterogeneous (normal), and strongly homogeneous. Progression-free survival was similar for patients with loss of RB protein expression and those with apparent overexpression of RB protein. Therefore, both staining patterns were considered abnormal. Patients with normal expression of both proteins (i.e., p53 negative and RB heterogeneously positive) had an excellent outcome, with no patient showing disease progression, whereas patients with abnormal expression of either or both proteins had a significant increase in progression (P = 0.04 and P = 0.005, respectively). These data support the stratification of T1 bladder cancer patients based on p53 and RB nuclear protein status and suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one and particularly both genes require more aggressive treatment.
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PMID:p53 and RB expression predict progression in T1 bladder cancer. 956 75

To analyze transforming growth factor-beta (TGF-beta) response during MCF-7 cell progression, early passage (MCF-7E, < 200 passage) and late passage (MCF-7L, > 500 passage) cells were compared. MCF-7E cells showed an IC50 of approximately 10 ng/ml of TGF-beta1, whereas MCF-7L cells were insensitive. MCF-7E cells contained approximately threefold higher levels of TGF-beta receptor type II (TbetaRII) mRNA than MCF-7L, but their TbetaRI levels were similar. MCF-7E parental cells showed higher TbetaRII promoter activity than MCF-7L cells, which could be attributed to changes in Sp1 nuclear protein levels. Receptor cross-linking studies indicated that the cell surface receptor levels parallel mRNA levels in both cell lines. Limiting dilution clones of MCF-7E cells were established to determine the heterogeneity of TbetaRII expression in this cell line, and they showed varying degrees of TbetaRII expression. Fibronectin was induced at higher levels in cells expressing higher TbetaRII levels. All three TGF-beta isoforms were detected in limiting dilution clones and parental cells, but TGF-beta1 was more abundant relative to TGF-beta2 or 3, and no correlation between TGF-beta isoform profile with TGF-beta sensitivity was found. MCF-7L cells were tumorigenic and formed xenografts rapidly and progressively, whereas MCF-7E parental and limiting dilution clonal cells showed transient tumor formation followed by regression. These results indicate that decreased TbetaRII transcription in breast cancer cells leads to a loss of TbetaRII expression, resulting in cellular resistance to TGF-beta which contributes to escape from negative growth regulation and tumor progression.
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PMID:Expression of transforming growth factor-beta receptor type II and tumorigenicity in human breast adenocarcinoma MCF-7 cells. 964 30

Substantial attention has been paid to the role of the toll-like receptor (TLR) ligands of late and their role in regulating the innate immune response. They serve as exogenous danger signals important in informing and driving the distal adaptive immune response to pathogens. Less clear has been the role of the nominal endogenous danger signals released and recognized in stressed cells following genotoxic or metabolic stress as occurs in progressively growing tumors. HMGB1 (high-mobility group B1) is a nuclear protein well characterized for its ability to modify DNA access to transcriptional proteins that is released from necrotic cells as well as secreted through the endosomal route from hematopoietic cells, serving as a late mediator of sepsis. It interacts with high-affinity RAGE (receptor for advanced glycation end products) and TLR2 receptors. Here we show that HMGB1 enhances interferon gamma release from macrophage (but not dendritic cell)-stimulated NK cells. This is effective only when coupled with other pro-inflammatory cytokines particularly with IL-2 in combination with IL-1 or IL-12. We have used this information to suggest that HMGB1, which also promotes epithelial migration and proliferation, drives repair in the absence or inhibition of other factors but enhances inflammation in their presence. The implications for tumorigenesis and tumor progression are quite important as they may be for other states of chronic inflammation.
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PMID:Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. 1560 95

T- and L-plastin are highly similar actin-bundling proteins implicated in the regulation of cell morphology, lamellipodium protrusion, bacterial invasion and tumor progression. We show that T-plastin localizes predominantly to the cytoplasm, whereas L-plastin distributes between nucleus and cytoplasm in HeLa or Cos cells. T-plastin shows nuclear accumulation upon incubation of cells with the CRM1 antagonist leptomycin B (LMB). We identified a Rev-like nuclear export sequence (NES) in T-plastin that is able to export an otherwise nuclear protein in an LMB-dependent manner. Deletion of the NES promotes nuclear accumulation of T-plastin. Mutation of residues L17, F21 or L26 in the T-plastin NES inhibits nuclear efflux. L-plastin harbors a less conserved NES and lacks the F21 T-plastin residue. Insertion of a Phe residue in the L-plastin NES specifically enhances its export activity. These findings explain why both isoforms exhibit specific distribution patterns in eukaryotic cells.
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PMID:Molecular basis for dissimilar nuclear trafficking of the actin-bundling protein isoforms T- and L-plastin. 1575 38

The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-beta signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-beta. SKI can also function as a transcriptional activator, targeting the beta -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.
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PMID:SKI pathways inducing progression of human melanoma. 1598 36

The emergence of hepatocellular carcinoma (HCC) is thought to be a stepwise process, with high-grade dysplastic nodules (HGDN) representing premalignant lesions arising in a background of cirrhosis. Earlier studies have revealed altered expression of transforming growth factor-alpha (TGF-alpha) (a mitogen capable of inducing hepatocarcinogenesis in mice) in HCC and its surrounding parenchyma. DNA topoisomerase II-alpha (Topo II-alpha) is a nuclear protein targeted by several chemotherapeutic agents and is overexpressed in HCC. The expression of both TGF-alpha and Topo II-alpha in putative preneoplastic hepatocytic lesions, however, has not been extensively studied. We examined the patterns of TGF-alpha and Topo II-alpha expression in noncirrhotic liver, liver cirrhosis, low-grade dysplastic nodules (LGDN), HGDN, and HCC to define the possible relationships of these markers to tumor progression. Paraffin sections from formalin-fixed material were immunostained with antibodies against TGF-alpha, Topo II-alpha, and Ki-67. Forty-six HCC, 17 HGDN, and 12 low-grade dysplastic nodules were identified in 52 cirrhotic livers from explanted or resected specimens. Nuclear staining for Ki-67 and Topo II-alpha was significantly increased in the progression from cirrhosis, through HGDN, to HCC, whereas the scores for TGF-alpha in these lesions showed an inverse relationship. In comparison with 18 HCC arising in noncirrhotic livers, the expression of TGF-alpha is significantly stronger in cirrhotic liver than in noncirrhotic parenchyma and its expression is also stronger in HCC arising in cirrhosis than in HCC arising in noncirrhotic parenchyma. The increased expression of Topo II-alpha and Ki-67 from HGDN to HCC, when compared with cirrhosis, suggests that HGDN is a precursor lesion in hepatocarcinogenesis. The inverse relationship between these proliferative markers and TGF-alpha expression in these lesions and stronger expression of TGF-alpha in HCC arising in cirrhosis suggest that TGF-alpha may play an important role in the early events of liver carcinogenesis.
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PMID:The expression of transforming growth factor-alpha in cirrhosis, dysplastic nodules, and hepatocellular carcinoma: an immunohistochemical study of 70 cases. 1746 Apr 50


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