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)

The cervical dysplasia and cancer of the uterine cervix of 82 patients have been studied by the cyto-fluorimetric technique. There were 46 patients with dysplasia of mild, moderate and severe degree and 36 patients with different histopathologic type cancer of the uterine cervix T1-2N0M0. DNA content was determined in cytological smears and scrapings of cervix uterus epithelium using luminescent microscope equipped with photometric device FMEI-1. The mean DNA content under dysplasia of cervix uterus reliably differed from that in control (3.504 +/- 0.054 and 4.715 +/- 0.051, respectively). The level of DNA content was heterogenic and elevated in cases of intraepithelial cancer and carcinoma in situ (8.369 +/- 0.84 and 10.098 +/- 0.28, respectively). This value was considerably higher than tumor progression (9,423 +/- 0.051).
 ...
PMID:[Cytofluorimetric research on the epithelium of the cervix uteri in malignancy]. 821 23

Neoplasia is a progression of molecular, cellular, and tissue changes starting with a critical cell mutation and advancing by clonal evolution, involving further multiple mutations and expanding mutated clones. This process is characterized by five general stages: latency, focal growth of normal-appearing but disorganized cells, abnormal-appearing cells (dysplasia), microinvasion, and finally, metastasis. The two driving forces of neoplastic progression in an epithelium are mutagenesis and mitogenesis. These forces frequently occur concurrently, produced by exposure of the epithelium to environmental and endogenous mutagens and mitogens. The major strategy of chemoprevention is to block the effects of both mutagens and mitogens during the early stages of predysplasia and dysplasia. Surrogate endpoint biomarkers (SEBs) are tissue, cellular, and molecular changes that correlate with the later development of cancer. Because of the savings in cost, labor, and time, SEBs are urgently needed to replace the use of cancer incidence reduction as the endpoint for chemopreventive agent clinical trials. The advent of computer-assisted cytometry allows each of the seven basic criteria of dysplasia to be individually assayed as an SEB. Since the dysplastic changes that characterize intraepithelial neoplasia are embodied in the causal pathway to invasive neoplasia, they are already validated as predictors of cancer incidence. More attention should be paid to the quality control of SEB assays, including control of variation in cell composition of tissue samples, assay protocol, instrumentation used, and observer performance. The dose-response relationship between a known chemopreventive agent and the SEB should also be evaluated. The Division of Cancer Prevention and Control, National Cancer Institute, has begun a program to test chemopreventive agents in short-term Phase II clinical trials using dysplasia-based SEBs. The SEBs are assayed, when possible, by computerized cytometry. Trials are being conducted for oral leukoplakia, cutaneous actinic keratosis, superficial bladder cancer, pulmonary metaplasia/dysplasia, cervical dysplasia (CIN III), and adenomatous colonic polyps.
 ...
PMID:Intraepithelial neoplasia, surrogate endpoint biomarkers, and cancer chemoprevention. 841 8

Infection of epithelial cells with human papillomavirus is an important early event in the development of cervical dysplasia. However, progression to overt malignancy appears dependent upon further genetic and/or epigenetic events. We have recently developed methodologies for the simultaneous analysis of loss of heterozygosity (LOH) at multiple PCR-based microsatellite loci using semiautomated fluorescent DNA sequencing technology to determine the locations of tumor suppressor genes which are inactivated during tumor progression. While examining 30 microsatellite loci for LOH on chromosomes 3p, 4, and 11q, we detected novel tumor-specific alleles indicative of microsatellite instability (MI). The methodology allowed rapid and accurate comparison of over 3000 genotypes from 89 primary tumors and 10 cervical carcinoma-derived cell lines and showed that five tumors (5.6%) and one human papillomavirus-negative cell line, C33A, had genetic features consistent with a replication error (RER+) phenotype as defined by MI at two or more loci. In each of the RER+ tumors, LOH was also observed at one or more loci on each of the three chromosomes examined. These findings suggest that defects in DNA repair-associated genes are rarely acquired and do not supersede allelic loss during cervical carcinogenesis. In addition, the semiautomated multiplex approach has proven unequivocal in the detection and interpretation of MI and should greatly accelerate the rapidity and accuracy of analysis of such defects in tumors. Moreover, the number of loci that can be relatively easily examined in this way will also allow a detailed statistical consideration of the importance of such events.
 ...
PMID:Analysis of replication error (RER+) phenotypes in cervical carcinoma. 864 Aug 35

Expression of splice variants of the CD44 adhesion molecule has been implicated in metastatic spread of various human tumor cells, including malignant lymphomas and colon, mammary, and gastric carcinomas, and has been correlated to a poor prognosis for the respective patients. To determine whether variant CD44 molecules might also contribute to the metastatic spread of cervical cancer, we analyzed the CD44 expression pattern in normal cervical epithelium and in low- and high-grade cervical dysplasia and compared it with invasive and metastasizing cervical cancers, including cell lines derived thereof by immunofluorescence and exon-specific PCR amplification of reverse-transcribed CD44 transcripts. We observed that normal cervical epithelium and dysplastic lesions express high levels of standard CD44 in the basal and spinous epithelial layers. CD44 molecules encompassing variant exons v5 and v6 are strongly expressed throughout the epithelium. Low levels of variants encompassing exon v7 are expressed in basal and spinous layers, with particular strength in the suprabasal layer. Low levels of epitopes encoded by v8 and v10 are expressed in the basal and spinous layers. In cervical cancers, including lymph node metastasis, we observed strong expression of v5 and v6, but almost no expression of v7, v8, and v10. Expression of the CD44 standard form appeared to be down-regulated in some cancers when compared to normal cervical epithelium. Thus, expression of variant CD44 molecules is related to distinct differentiation of mucosal squamous epithelia in the female genital tract. No correlation of the expression of variant CD44 isoforms, including the v7-v8 fusion epitope with tumor progression or lymphatic spread, was observed.
 ...
PMID:Expression of CD44 splice variants in normal, dysplastic, and neoplastic cervical epithelium. 981 3

Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.
 ...
PMID:Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. 1566 16

CDC6 and MCM5 play essential roles in eukaryotic DNA replication. Several studies have highlighted the potential of these proteins as molecular markers of dysplastic and malignant cells in histopathological diagnosis. The mode of expression of CDC6 and MCM5 mRNA and their significance in normal, dysplastic and malignant cervical cells remains to be elucidated. Using a quantitative real-time RT PCR assay, we compared CDC6 and MCM5 mRNA expression in normal cervical epithelium, cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. Our study cohort comprised 20 normal cervical biopsies, 20 CIN3 and eight invasive squamous cell carcinomas. All samples were formalin fixed and paraffin embedded. Total RNA was extracted and analysed for expression of GAPDH, CDC6 and MCM5 using real-time quantitative TaqMan RT-PCR. A linear increase in MCM5 and CDC6 mRNA expression is observed in normal cervix, CIN3 and invasive cervical carcinoma. The overall difference in MCM5 mRNA expression in the normal cervix, CIN3 and invasive cohort groups is highly statistically significant (P=0.001). An increase in CDC6 mRNA expression in CIN3 and invasive cervical squamous cell carcinoma was observed; however, the overall difference between cohort groups was not found to be statistically significant (P=0.104). Increased transcription of MCM5 and CDC6 occurs as a consequence of cervical neoplastic progression. This pattern of increased mRNA expression in CIN3 and invasive cervical carcinoma directly correlates with findings at the phenotypic protein expression level. This study further confirms the importance of MCM5 and CDC6 in malignant transformation and in the pathogenesis of cervical dysplasia.
 ...
PMID:Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. 1569 26

Cervical cancer, a potentially preventable disease, remains the second most common malignancy in women worldwide. Human papillomavirus is the single most important etiological agent in cervical cancer, contributing to neoplastic progression through the action of viral oncoproteins, mainly E6 and E7, which interfere with critical cell cycle pathways, p53 and retinoblastoma. However, evidence suggests that human papillomavirus infection alone is insufficient to induce malignant changes and that other host genetic variations are important in the development of cervical cancer. This article will discuss the latest molecular profiling techniques available and review the published literature relating to their role in the diagnosis and management of cervical dysplasia and cancer. It is hoped that these techniques will allow the detection of novel biomarkers at DNA, RNA, microRNA and protein levels, which may ultimately play a role in facilitating early disease diagnosis and in predicting response to therapies, thus allowing the development of personalized treatment strategies.
 ...
PMID:Molecular profiling of cervical neoplasia. 1651 81