Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study mechanisms involved in evolution of soft tissue sarcomas, we compared DNA ploidy and karyotypes at different stages of their disease in two patients with myxoid liposarcomas (MLS), one with a fibrosarcoma (FS), and two with rhabdomyosarcomas (RMS). None of the MLS samples revealed clearcut histologic changes in later samples as compared to their primaries, and the DNA ploidy in all samples was diploid. In one patient karyotypes at four different times during the 19 yr of his disease all revealed a t(11;12) (p15;q13), but additional clonal chromosomal abnormalities occurred only in later recurrences. In another patient the karyotypes obtained in the 26th and 28th yr of his disease were similar and included the t(12;16) (q13;p11), characteristic of MLS. A comparison with karyotypes of six other MLS patients at different disease stages suggests that the presence of a t(12;16) may correlate with less aggressive clinical behavior. The histology of the FS remained low-grade and the DNA ploidy diploid. The karyotype, however, showed evolution. In both MLS and FS, chromosomal changes thus seem to be a more sensitive marker for tumor progression than histologic changes or DNA ploidy. In one embryonal RMS, karyotypes obtained 7 and 11 yr after the primary diagnosis were different but clearly had a common "progenitor." In one alveolar RMS, the primary and the synchronous lung and lymph node metastases all revealed a t(2;13). The findings in RMS suggest that polyploidization is an early event in tumor evolution, especially in the alveolar subtype, which may be followed by additional chromosomal changes. In addition, DNA ploidy was measured in eight other RMSs. Among the RMSs the embryonal subtype was characterized by DNA aneuploidy, whereas three of the alveolar cases were in the tetraploid range and one was peridiploid. In local recurrences and in metastases changes in DNA index were observed in half the cases.
 ...
PMID:DNA ploidy and karyotype in recurrent and metastatic soft tissue sarcomas. 134 14

The P15 gene (MTS2) encodes a cyclin-dependent kinase (CDK) inhibitor with considerable sequence identity and biochemical similarity to the CDK inhibitor p16. It is closely linked to the P16 gene (MTS1) and is homozygously deleted in many tumor cell lines. These features suggest that p15 may be a tumor suppressor. We have determined the genomic structure of P15 and examined its pattern of mRNA expression. In addition, we have shown that ectopic expression of p15 inhibits growth of tumor-derived cell lines. We have also searched for P15 mutations in tumor cell lines and in 9p21-linked melanoma kindreds. Other than the previously described homozygous deletions, no mutations of P15 were found. Collectively, these observations suggest a role for p15 in growth regulation, but a limited role for p15 in tumor progression.
 ...
PMID:Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. 767 59

Expression of cell cycle regulatory genes in mouse lung was investigated in transgenic models for Clara cell transformation. Clara cells were transformed by generating transgenic mice in which the SV40 large T antigen was expressed under the control of the mouse Clara cell M(r) 10,000 protein promoter. The resulting lung tumors express the large T antigen in normal Clara cells and in tumors, and these tumors express reduced levels of CC10 mRNA. The expression of cell cycle regulatory protein, p53, and the cyclin-dependent kinase inhibitors was analyzed by Northern blot analysis and in situ hybridization throughout the progression of Clara cell transformation in the lung. Increases in specific cyclin-dependent kinase inhibitor steady-state mRNA levels were detected in p15, p18, p27, and p57 during tumor progression. The expression of p15, p57, and p21 mRNAs were verified by in situ hybridization. Using this approach, regulatory genes have been identified that may be involved in the regulation of Clara cell differentiation.
 ...
PMID:Cyclin-dependent kinase inhibitor expression in pulmonary Clara cells transformed with SV40 large T antigen in transgenic mice. 904 Sep 36

Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
 ...
PMID:Alterations in DNA methylation: a fundamental aspect of neoplasia. 933 76

Chromosome 11p15 has attracted considerable attention because of the biological importance of this region to human disease. Apart from being an important tumor suppressor locus showing loss of heterozygosity (LOH) in several adult and childhood cancers, 11p15 has been shown by linkage analysis to harbor the gene(s) for the Beckwith-Wiedemann syndrome. Furthermore, the clustering of known imprinted genes in the 11p15.5 region suggests that the target gene may also be imprinted. However, positional cloning efforts to identify the target genes have been complicated by the large size (approximately 10 Mb) and complexity of LOH at 11p15. Here, we have analyzed 94 matched normal and breast tumor samples using 17 polymorphic markers that map to 11p15.5-15.4. We have defined precisely the location of a breast tumor suppressor gene between the markers D11S1318 and D11S4088 (approximately 500 kb) within 11p15.5. LOH at this region occurred in approximately 35-45% of breast tumors analyzed. In addition, we have fine-mapped a second, critical region of LOH, that spans the markers D11S1338-D11S1323 (approximately 336 kb) at 11p15.5-p15.4, that is lost in approximately 55-60% of breast tumors. There is a striking correlation between the loss of the two 11p loci and the clinical and histopathological features of breast tumors. LOH at region 1 correlated significantly (P = 0.016) with early events in malignancy and invasiveness. In contrast, the loss of the more proximal region 2, is highly predictive (P = 0.012) of aggressive metastatic disease. Thus, two distinct tumor suppressor loci on chromosome 11p15 may contribute to tumor progression and metastasis in breast cancer. The fine mapping of this intriguing chromosomal region should facilitate the cloning of the target genes and provide critical clues to understanding the mechanisms that contribute to the evolution of adult and childhood cancers.
 ...
PMID:Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis. 953 95

Neoplastic transformation, cancer progression, and metastasis are determined by a series of well-defined changes that take place in target tissue cells. Genetic alterations associated with human prostate carcinogenesis are not well defined. Some chromosomal changes, including gain of chromosomes 7, 12, 17, and X and loss of heterozygosity in chromosomes 8p, 10q, 16q, 17p, and 18q, have been reported. We examined five newly established and eight previously established prostate cancer cell lines before and after subcutis and orthotopic injection into nude mice and observed that structural alterations of chromosome 5 were present in all of the cell lines except the parental LNCaP. The fluorescence in situ hybridization preparations with the use of whole chromosome 5 DNA painting probe confirmed our Giemsa-banding data. Alterations of chromosome 5 consisted of t(1;5)(p36;q15), t(5;?)(p11;?), del(5)(q23q35) in the SP2964(= ARCaP) cell line; t(5;8)(p15;q12), i(5)(p10), t(5;15)(q11;p11) in the SP3031 cell line; t(5;?;15) (q15;?;p11), t(5;7;14)(q31;p11-q32;q11), in the SP3173 and SP3241 cell lines (derived from the same patient); del(5)(q23-33) and t(5;7;14)(q31;p11-q32;q11) in the SP3316 cell line; t(3;5)(q21;q35) in the SP2884 cell line; t(5;5)(p15;q11) in the SP2356 cell line; i(5)(p10),t(5;?)(q23;?) in the DU-145 cell line; and i(5)(p10), t(5;?)(q11;?) and t(2;5)(q15;q15) in the PC-3 cell line. Because, in most cases, alteration of chromosome 5 resulted in the partial or complete loss of 5q, we conjectured that 5q might contain one or more tumor-suppressor genes for human prostate cancer development.
 ...
PMID:Structural alterations of chromosome 5 in twelve human prostate cancer cell lines. 979 73

We prospectively analyzed p15 methylation patterns in 25 surgically resected tumors and 130 plasma, serum, and buffy coat samples from hepatocellular carcinoma (HCC) patients, controls with chronic hepatitis/cirrhosis, and healthy subjects. Using methylation-specific PCR, we demonstrated for the first time p15 promoter methylation in 64% of tumors and 25% (4 of 16) of patients' plasma and serum samples. Concurrent p15 and p16 methylation was shown in 48% of tumors, and p15/p16 methylation was detected in the plasma/serum of 92% (11 of 12) of patients. Of note, 75% of 12 patients with concurrent tumor methylation developed clinical metastasis/recurrence (P = 0.027). In buffy coat samples, p15 methylation was detected in all eight patients with tumor p15 methylation, suggesting the presence of circulating tumor cells. None of the control samples were methylation positive. Our data underscore the important role(s) of p15 and p16 methylation in hepatocarcinogenesis and tumor progression. Among 92% (23 of 25) of patients with tumor p15/p16 methylation, circulating tumor DNA and HCC cells were detected in the peripheral blood of 87% (20 of 23) of patients. The combination of these epigenetic markers may prove valuable for noninvasive HCC diagnosis and disease monitoring.
 ...
PMID:Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. 1099 38

The aims of this study were to compare genetic aberrations in primary soft-tissue sarcomas and their local recurrences and to evaluate the genetic changes occurring during tumor progression. A primary soft-tissue sarcoma and its subsequent local recurrence were analyzed in 20 tumor pairs by comparative genomic hybridization. The samples were obtained before application of radio- or chemotherapy. Copy number aberrations were detected in 50% of the primary tumors and in 70% of the local recurrences. In primary tumors, the mean number of changes was 2.45 (range, 0 to 11) whereas in local recurrences, it was 5.05 (range, 0 to 17). The mean increase of changes from primary tumor to local recurrence was 2.6 per tumor pair (P =.02). Gains predominated over losses in both primary tumors and their local recurrences. The number of high-level amplifications was twofold in local recurrences. The most frequent gain affected 5p14-p15.1 (10% of primary tumors, 25% of local recurrences) and the most frequent loss, 9p (9p21-pter in 5% of primary tumors; 9p22-pter in 30% of local recurrences). In conclusion, our results show an increase in the number of genetic changes in local recurrences, due to tumor progression. Loss at 9p and gains at 5p and 20q were more frequent in local recurrences, and high-level amplification of 18p11.3 was not detected in any of the primary tumors. Although all these alterations were not specific to local recurrences, they may represent changes important during tumor progression.
 ...
PMID:Primary soft tissue sarcoma and its local recurrence: genetic changes studied by comparative genomic hybridization. 1159 67

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma, a cancer of which the incidence has been increasing at an alarming rate in Western countries. p16(INK4a) lesions occur frequently in esophageal adenocarcinomas but their role in neoplastic progression is not well understood. We detected 9p21 loss of heterozygosity, p16 CpG island methylation, and p16 mutations in biopsies from 57%, 61%, and 15%, respectively, of 107 patients with BE. In contrast, no mutations were found in p14(ARF) or p15, and methylation was found in only 4% and 13%, respectively. >85% of Barrett's segments had clones with one (p16+/-) or two (p16-/-) p16 lesions. Both p16+/- and p16-/- clones underwent extensive expansion involving up to 17 cm of esophageal mucosa. The prevalence of established biomarkers in BE, such as 17p (p53) loss of heterozygosity, aneuploidy, and/or increased 4N (tetraploid) populations, increased from 0% to 20% to 44% in patients whose biopsies were p16+/+, p16+/-, and p16-/-, respectively (P < 0.001). Barrett's segment lengths also increased with change in p16 status with a median of 1.5, 6.0, and 8.0 cm for patients with p16+/+, p16+/-, and p16-/- biopsies, respectively (P < 0.001). We conclude that most Barrett's metaplasia contains genetic and/or epigenetic p16 lesions and has the ability to undergo clonal expansion, creating a field in which other abnormalities can arise that can lead to esophageal adenocarcinoma.
 ...
PMID:p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. 1171 61

Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the GIS checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin-catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand-growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFkappaB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti-inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.
 ...
PMID:Atherosclerosis and cancer: common molecular pathways of disease development and progression. 1179 76


1 2 3 4 Next >>