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 high frequency of mutation, deletion, and promoter silencing of the gene encoding p16(INK4A) (p16) in premalignant dysplasias and squamous cell carcinomas (SCC) of epidermis and oral epithelium classifies p16 as a tumor suppressor. However, the point during neoplastic progression at which this protein is expressed and presumably impedes formation of an SCC is unknown. Induction of p16 has been found to be responsible for the senescence arrest of normal human keratinocytes in culture, suggesting the possibility that excessive or spatially abnormal cell growth in vivo triggers p16 expression. We examined 73 skin and oral mucosal biopsy specimens immunohistochemically to test this hypothesis. p16 was not detectable in benign hyperplastic lesions, but instead was expressed heterogeneously in some dysplastic and carcinoma in situ lesions and consistently at areas of microinvasion and at superficial margins of advanced SCCs. p16-positive cells in these regions coexpressed the gamma2 chain of laminin 5, identified previously as a marker of invasion in some carcinomas. Normal keratinocytes undergoing senescence arrest in culture proved to coordinately express p16 and gamma2 and this was frequently associated with increased directional motility. Keratinocytes at the edges of wounds made in confluent early passage cultures also coexpressed p16 and gamma2, accompanying migration to fill the wound. These results have identified the point during neoplastic progression in stratified squamous epithelial at which the tumor suppressor p16 is expressed and suggest that normal epithelia may use the same mechanism to generate non-dividing, motile cells for wound repair.
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PMID:Co-expression of p16(INK4A) and laminin 5 gamma2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. 1287 69

An in vitro model, based on normal (primary) human astrocytes (NHAs), was used to investigate the nature of the selection pressures for events that occur during the progression of astrocyte-derived tumors and, in particular, the potential role of proliferative life span barriers (PLBs). As with fibroblasts, NHAs senesced with elevated p21(WAF1) and senescence-associated beta-galactosidase activities. Unlike fibroblasts, replicative senescence (M1) occurred much earlier, after approximately 20 pd and was not bypassed by hTERT expression. Abrogation of p53 function, by expression of human papillomavirus type 16 E6, led to an extension of life span, implying that replicative senescence in NHAs was p53-dependent but telomere-independent. human papillomavirus type16 E6 expression promoted additional growth of up to 12 pd, until a second telomere-independent PLB (termed M(INT)) was imposed associated with elevated p16(INK4A) levels. A proportion of cells escaped from M(INT) lost p16(INK4A) expression and achieved approximately an additional 25 pd until a crisis-like third PLB (M2) was reached. Expression of hTERT in post-M(INT) cells allowed these cells to become immortal and bypass this third PLB. The in vitro PLBs appear, in order of occurrence, dependent upon p53, p16(INK4A), and telomere erosion, a situation that mirrors an equivalent order of mutational events during tumor progression in vivo. This study describes a model that provides a plausible explanation for the selective pressures driving mutational events in this tumor type and provides direct evidence of a p53-dependent, telomere-independent PLB.
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PMID:A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development. 1294 6

This study investigates differences in expression of the cell cycle/growth activation markers p53, p16, and p27, and their relationship with nerve sheath cell and proliferation markers among plexiform neurofibromas (PNF), NF1-related and non-NF1 MPNSTs of different histologic grades and between benign-appearing and malignant areas in the MPNSTs associated with PNFs. Formalin-fixed, paraffin-embedded archival tissue from PNFs and MPNSTs were immunostained using the avidin-biotin-complex method with antibodies to S-100 protein (S-100), Leu7 (CD57), CD34, p16, p27, p53, Mib-1, and topoisomerase II-alpha (TopoIIalpha), with appropriate controls. All PNFs and most low-grade MPNSTs displayed diffuse or focal reactivity for S-100, Leu7, CD34, p16, and p27 and negative reactivity for p53, Mib-1, and TopoIIalpha. Most high-grade MPNSTs displayed decreased or negative reactivity to S-100, Leu7, CD34, p16, and p27 but increased reactivity to p53 (59%), Mib-1 (72%), and TopoIIalpha (72%). In addition, combined nuclear and cytoplasmic (nucleocytoplasmic) p27 staining, which was not seen in the PNF or low-grade MPNST, was observed in 33% of high-grade MPNSTs. These findings suggest that p53, p16, and p27 may be involved in tumor progression in the PNF-MPNST sequence. However, alterations in p53, p16, and p27 do not distinguish between low-grade MPNST and PNF, including PNF adjacent to high-grade MPNST. Although p53, p16, and p27 are unlikely to be reliable markers for early detection of tumor progression in MPNST, p53 reactivity was more frequent in NF1-associated high-grade MPNST and appeared to be a marker for high tumor grade. Combining immunohistochemical stains with histologic grading with careful examination of mitotic activity may provide insight into the progression of peripheral nerve sheath tumors.
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PMID:Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. 1450 95

Ependymomas are glial neoplasms whose clinical behavior is difficult to predict based on histology alone. Recently, a comparative genomic hybridization study identified frequent chromosome 9p and 13q losses in anaplastic ependymomas, suggesting that p16 and RB alterations may be involved in tumor progression. In order to test this hypothesis further, 101 myxopapillary, conventional, and anaplastic ependymomas (51 spinal and 50 intracranial tumors) were tested for RB and p16 deletions using fluorescence in situ hybridization. Clinical follow-up, ranging from 2 to 198 months (median 46 months), was obtained in 90 cases (91%). RB and p16 deletions were seen in 22 of 92 (24%) and 22 of 89 (25%) informative cases, respectively. Polysomies were more frequent in the grade I and II spinal tumors, consistent with prior reports of increased aneuploidy in such cases. No significant genetic associations were seen with tumor grade, recurrence, or death, suggesting that 9p and 13q deletions do not play a prominent role in the malignant progression of ependymomas, as has been implicated in other glioma subtypes.
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PMID:9p21 and 13q14 dosages in ependymomas. A clinicopathologic study of 101 cases. 1463 64

Multiplex methylation-sensitive PCR was employed in studying the methylation of CpG islands in the RB1, p16/CDKN2A, p15/CDKN2B, p14/ARF, CDH1, HIC1, and N33 5' regions in non-small cell lung cancer (51 tumors). Methylation was observed for the two suppressor genes involved in controlling the cell cycle through the Cdk-Rb-E2F signaling pathway, RB1 (10/51, 19%) and p16 (20/51, 39%). The highest methylation frequencies were established for CDH1 (72%) and HIC1 (82%). The CpG islands of p14 and p15 proved to be nonmethylated. At least one gene was methylated in 90% (46/51) tumors and no gene, in 10% (5/51) tumors. In addition, the genes were tested for methylation in peripheral blood lymphocytes of healthy subjects. Methylation frequency significantly differed between tumors and normal cells in the case of RB1, p16, CDH1, HIC1, and N33. Gene methylation frequency was tested for association with histological type of the tumor and stage of tumor progression. Methylation index of a panel of tumor suppressor genes was established for groups of tumors varying in clinical and morphological parameters.
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PMID:[Profile of methylation of certain tumor growth suppressing genes in non-small cell lung cancer]. 1471 93

Melanoma prognosis is based on histological criteria such as tumor thickness (measured by Breslow index), level of invasion (Clarck's level), presence of ulceration and number of mitoses per mm2. However, these parameters do not provide a precise prognosis in all cases: thin melanomas may develop metastases and thick melanomas may remain focalized for many years. For these reasons, the search for other prognostic factors is still ongoing. Many molecules play a part in the invasiveness and metastatic dissemination of melanoma have now been identified. Expression of these molecules has been studied in primary melanoma and correlated with prognosis. An increase in the number of cells positive for Ki67 (detected by Mib1), cycline A, cycline D, p35, MMp-2, beta1 and beta3 integrins, osteonectin, the presence of an intense inflammatory infiltrate and capillary invasion are considered as factors of poor prognosis as well as the decrease in p16, p27, Melan A and nm23. The significance of CD44 modifications is still controversial. Only a small number of these different proteins has a prognostic value independent of tumor thickness. These results need to be confirmed on larger series of patients. Additional hope is given to new techniques such as the analysis of the genes implied in tumor progression by microarray technique in such a way as to provide a molecular map of each tumor.
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PMID:[Molecular markers associated to prognosis of melanoma]. 1472 37

Little is known about the correlation between the loss of p16 expression and tumor progression in familial melanoma; no systematic study has been conducted on p16 expression in melanocytic tumors from patients carrying germline CDKN2A mutations. We analyzed 98 early primary lesions from familial patients, previously tested for germline CDKN2A status, by quantitative immunohistochemistry using 3 p16 antibodies. We found that p16 expression was inversely correlated with tumor progression and was significantly lower in melanomas, including in situ lesions, than in nevi. Of other features analyzed, tumor thickness showed the most significant correlation with p16 levels. Lesions from mutation-negative patients displayed combined nuclear and cytoplasmic staining. However, some mutation-positive lesions (ie, G101W, 113insR, M53I, R24P, and 33ins24), including benign nevi, showed nuclear mislocalization, confirming previous studies suggesting that subcellular distribution indicates functional impairment of p16.
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PMID:Expression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients. 1474 21

Cell proliferation and apoptosis are controlled by tightly orchestrated signaling pathways that culminate in transcriptional activation/repression of multiple proteins. Dysregulation of cell cycle and/or apoptosis control may lead to genomic instability, neoplastic transformation and tumor progression. Under certain conditions, some hexavalent chromium [Cr(VI)] compounds are toxic and carcinogenic in the human respiratory tract, and we have shown that they induce apoptosis and/or cell cycle arrest in a p53-dependent fashion. There is increasing evidence linking extracellular signal-regulated kinase (ERK) activation with the DNA damage response, by both p53-dependent and -independent mechanisms. Here, the aim was to study the effect of Cr(VI) transcriptional regulation of key cell cycle inhibitors and pro- and anti-apoptotic proteins, as well as the role of ERK activation in the Cr(VI) genotoxic response. Diploid human lung fibroblasts were incubated with 3-9 uM Na2CrO4, and RNA was isolated at 4, 8, and 24 h, as well as 24 h after Cr(VI) exposure was terminated (recovery). mRNA expression was quantitated by RNase protection assay with a 32P-labeled multi-transcript probe containing gene sequences for the cdk inhibitors, p21waf1/cip1, p27kip1, p16INK4a, p15INK4b; the pro-apoptotic proteins bcl-XS and bax; the anti-apoptotic proteins bcl-W, bcl-XL, and bcl2, GADD45, and cyclin A. In general, bcl-W and bcl-XL expression were both downregulated after Cr exposure, to around 50% at 24 h, which was more pronounced after the recovery period. At Cr(VI) concentrations < or = 6 uM, bcl2 expression was upregulated. Of particular interest is that bax expression was reduced, in a dose and time-dependent fashion, however that of bcl-XS was elevated by nearly 3-fold after 8 h, and declined to control levels at the end of the recovery period. Expression of GADD45 and p21 were both upregulated by 2-fold at 8 h, but declined to control levels during recovery. Neither the expression of p27 nor that of p16 were apparently affected by Cr(VI) exposure, however the expression of p15 was markedly increased after exposure to all concentrations of Cr(VI). Finally, the expression of cyclin A was decreased after 24 h Cr(VI) exposure. Cr(VI) induced a transient burst of ERK activity (2-6-fold over control) around 0.5-3 h after exposure. However, inhibition of ERK activation with PD98059 had no effect on the Cr-induced alterations in gene expression. Moreover, Cr(VI)-induced clonogenic lethality, as assessed after 24 h exposure to 1 and 2 uM Cr(VI), was also not affected by ERK inhibition. These data suggest that both p53-dependent and -independent apoptotic and growth-inhibitory pathways are markedly affected by Cr(VI) exposure. However, the ability of Cr(VI) to affect key apoptotic and growth arresting genes, and thus clonogenic lethality, appears to be independent of ERK. Continued investigation into the cellular and molecular mechanisms of Cr(VI)-induced cell cycle and apoptosis control should further the understanding of Cr(VI)-associated carcinogenesis.
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PMID:Induction of pro-apoptotic and cell cycle-inhibiting genes in chromium (VI)-treated human lung fibroblasts: lack of effect of ERK. 1497 55

Vascular endothelial growth factor (VEGF) expression has been suggested to correlate with intratumoral microvessel density, tumor advancement and prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies have showed that disruption of cell cycle regulator p16 is related to oncogenesis and tumor progression in ESCC. We hypothesized that VEGF expression in ESCC is reflected by abnormalities in the p16(INK4a) gene. To clarify the regulatory role of p16(INK4a) in VEGF expression in vitro, we transferred the p16(INK4a) gene into a p16(INK4a)-deleted ESCC cell line and observed changes in VEGF expression. Furthermore, we immunohistochemically assessed the expression of the cell cycle regulators (p16, p53 and RB) and VEGF in 90 surgically resected specimens of ESCC. Introduction of p16(INK4a) cDNA by the p16 expression vector significantly suppressed cell proliferation in the p16(INK4a)-deleted cell line TE8 (p < 0.0001). VEGF secretion by TE8 cells transfected with the p16(INK4a) vector was significantly suppressed as compared to non-transfected TE8 cells (p < 0.0001) and TE8 cells transfected with a control vector (p = 0.0015). The immunohistochemical studies of ESCC primary tumor specimens showed that loss of p16 expression was significantly correlated with VEGF-positive expression (p = 0.0004). The cumulative postoperative survival rate in the group with p16-positive and VEGF-negative expression was significantly higher than in the other groups. Neither p53 nor RB expression had any impact on outcome. Aberrant p53 expression tended to be associated with VEGF expression, but the trend did not reach statistical significance. Our study demonstrated that VEGF expression was correlated with p16 expression in ESCC. Our results suggest that p16 may have a regulatory role in VEGF expression in ESCC.
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PMID:Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus. 1499 68

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.
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PMID:Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. 1509 8


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