Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common prostatic carcinoma consists of two different types with respect to development, spread, histopathology, morphogenesis and prognosis. These are the carcinoma of the dorso-peripheral zone and the tumor which is located in the antero-central zone. The first one corresponds to the clinically manifest prostatic carcinoma, the latter is identical to the prostatic carcinoma incidentally found by the pathologist examining unsuspicious prostatic tissue from transurethral resection or simple prostatectomy. The antero-central tumor growths to the ventral area and infiltrates the apex and bladder neck frequently. It is biologically not as important as the tumor of the dorso-peripheral zone showing a lower grade of malignancy in the majority of cases. In 2 of 3 cases, however, there are one or more coexisting carcinomas in other, frequently dorso-peripheral zones. Therefore the risk of the individual patient can not precisely be estimated. The carcinoma of the dorso-peripheral zone does predominate by frequency and biological potency. The incidence of positive lymph nodes strongly increases when seminal vesicle invasion is found. The disturbance of the epithelial-stromal interaction is the starting point of carcinogenesis. In the first step, PIN results of an intraductal proliferation of atypical epithelial cells, whereas atypical hyperplasia develops from an overwhelming proliferation of tubular glands with progressive decrease of basal cells. Based on the topographical and histological relationships the role of PIN as a precursor lesion of the dorso-peripheral prostatic carcinoma is considered, whereas atypical hyperplasia is thought to represent the preneoplastic state of the incidental and antero-central prostatic carcinoma, respectively.
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PMID:[Pathology of prostatic carcinoma: new approaches to its development and biological significance]. 751 3

Prostatic cancer is the second most frequent cancer in men in industrialised countries. The histological analysis of its initial development demonstrates the existence of precancerous lesions, PIN. The initial presence of several different cell populations accounts for the development of contingents of hormone-sensitive and hormone-resistant cells. The presence of numerous neuroendocrine cells appears to be a factor of poor prognosis. Hormones are intimately involved in the development of prostatic cancer and are an integral part of its treatment. Progress in molecular biology has furthered out knowledge of this disease. In particular, growth factors such as EGF and FGF are particularly involved and are starting to have a clinical application. The oncogene and anti-oncogene system is currently being explored (particularly p53 abd BCL 2). They are the basis for carcinogenesis and analysis of these factors will allow a better approach to the mechanisms of tumour induction and development.
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PMID:[Cancer of the prostate. 2. Physiology and cellular development]. 771 57

Prostatic intraepithelial neoplasia (PIN) is regarded as the most important premalignant lesion of prostatic epithelium. The aim of this investigation was to find clues to formal pathogenesis of prostatic cancer. For this purpose DNA ploidy (determined by means of image cytometry [ICM] using 4-microns-thick Feulgen-stained paraffin sections) of PIN and invasive carcinoma was compared. Prostatic tissue of 72 patients (mean age, 67.5 years; 82 areas with carcinoma and 71 areas with PIN) was examined. In 44 cases PIN and carcinoma were coexistent in the same prostates, the PIN grade being high in 77% of these cases (P < .05). In higher-grade PIN and higher-grade carcinoma the c-values, 2.5c-exceeding-rate, and aneuploidy rate increased (P < .01). Carcinomas associated with diploid PIN (either low or high grade) showed diploidy and aneuploidy in an equal number of cases, whereas 70% of aneuploid PIN cases (all high grade) were associated with aneuploid invasive carcinomas (P < .01). Conversely, in 71% of the cases with aneuploid carcinoma the coexistent PIN (either low or high grade) was diploid. Our findings show that aneuploidy can be acquired at a preinvasive stage of carcinogenesis in the prostate and suggest that aneuploid high-grade PIN might be regarded as a precursor of some but not all aneuploid prostatic carcinomas. Image cytometry analysis seems to be a promising method for further subclassification of high-grade PIN lesions into groups with putatively lower or higher risk. However, further investigation is necessary to confirm the clinical importance of these results.
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PMID:Comparison of DNA ploidy in prostatic intraepithelial neoplasia and invasive carcinoma of the prostate: an image cytometric study. 820 Jun 45

High-grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence to date. The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma. Its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. PIN is associated with progressive abnormalities of phenotype and genotype intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is progressive gain or loss of a wide variety of biomarkers, including morphometric markers, differentiation markers, stromal markers, growth factors and associated receptors, oncogenes, tumor suppressor genes, and chromosomes. Abnormalities in expression of most biomarkers are amplified in the progression from high-grade PIN to localized cancer, metastatic cancer, and hormone-refractory cancer. Oncogenesis of prostatic carcinoma probably occurs through the selection of several genetic changes, each modifying the expression or function of genes controlling cell growth and differentiation. Further studies are needed to evaluate the function and prognostic value of oncogene expression in the normal, preneoplastic, and neoplastic prostate.
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PMID:Molecular biology of prostatic intraepithelial neoplasia. 870 Aug 1

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and is divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic cancer (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 27 cases with PCA were analyzed for p53 mutation in exons 5 - 8 by single-strand conformation polymorphism of polymerase chain reaction-amplified DNA fragments (PCR-SSCP) followed by direct sequencing. These patients received total prostatectomy (27 cases). After a review of histologic sections, DNA was extracted from 193 locations; 111 lesions from 27 cases with HGPIN (75 lesions from non-transition zone and 36 from transition zone), 55 lesions from 27 cases with PCA (30 lesions from non-transition zone and 25 from transition zone), and 27 from 27 benign glands. Analysis revealed 27 mutations of the p53 gene in 24 lesions from 12 cases. Benign glands adjoining PIN and / or PCA had no mutations. All mutations were point mutations: 17 missense, 7 silent, and 2 nonsense. Mutations were detected in 6 cases (22.2%) or 13 of 111 lesions (11.7%) with HGPIN and 8 cases (29.6%) or 11 of 55 lesions (20.0%) with PCA. In a given case, HGPIN and PCA lesions had different p53 mutations from each other, suggesting multiclonal development of prostatic precancerous lesions. The frequency of p53 mutation of PCA was significantly higher in the non-transition zone (33.3%) than in the transition zone (4%), and higher in the stage T3 cases (30.3%) than in the stage T2 cases (4.5%, 1 of 22 lesions) (both P < 0.05). Frequency of p53 mutation of PIN in the non-transition zone (14.7%) was higher than that in the transition zone (5.6%), although the difference was not significant. The frequency rate of p53 mutation in HGPIN close to PCA ( </= 2 mm) was significantly higher (24%) than that in HGPIN lesions > 2 mm from PCA (3%). All these findings indicate that the p53 gene mutations are involved in prostatic carcinogenesis and explain why the non-transition zone is the predominant site of PCA.
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PMID:p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens from non-transition and transition zones. 1101 Nov 23

Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (>3-fold) as well as protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we studied the effect of oral consumption of DFMO on development of prostate carcinogenesis and surrogate end point biomarkers related to prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment resulted in the marked reduction in the protein expression of proliferation cell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The protein expression of antimetastases markers, i.e., E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screening of novel drugs and chemopreventive regimens for potential human use.
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PMID:Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice. 1101 39

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate specific antigen. PIN is characterized by progressive abnormalities of phenotype which are intermediate between normal prostatic epithelium (NP) and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma (PCa), according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via the suppression of vascular endothelial growth factor (VEGF) production. It is likely that PCa might also arise from precursor lesions other than high-grade PIN (low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy).
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PMID:Prostatic intraepithelial neoplasia and prostate cancer. 1209 35

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate-specific antigen. PIN is characterized by progressive abnormalities of phenotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma, according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via suppression of vascular endothelial growth factor production. Prostatic carcinoma is also likely to arise from precursor lesions other than high-grade PIN such as low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy.
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PMID:Precancerous lesions and conditions of the prostate: from morphological and biological characterization to chemoprevention. 1209 42

Because prostate cancer has a long latency and high incidence, it is a good target for chemoprevention by agents such as retinoids, antiandrogens, antiestrogens, and vitamin D analogs. Phase II chemoprevention trials are frequently conducted on cohorts of patients with previous cancers or premalignant lesions who are scheduled for prostate cancer surgery; such trials are currently in progress with several agents. Prostatic intraepithelial neoplasia (PIN) can be used as a surrogate endpoint biomarker for prostate cancer incidence. Studies of men with high-grade PIN (HGPIN) are particularly useful in that they require a much smaller cohort of 200-400 patients instead of the 18 000 patients required for typical Phase III trials. Even with a smaller sample size, statistically significant evidence of cancer prevention is achieved due to the high probability of HGPIN progressing to cancer (35-55%). A Bayesian sequential monitoring system allows interim analysis of biomarker modulation as early as the completion of 30 patients. Putting all these strategies together will help inhibit, delay, or modulate the natural history of prostate carcinogenesis.
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PMID:Strategies for chemoprevention of prostate cancer. 1249 54

Somatic inactivation of the glutathione S-transferase-pi gene (GSTP1) via CpG island hypermethylation occurs early during prostate carcinogenesis, present in approximately 70% of high-grade prostatic intraepithelial neoplasia (high-grade PIN) lesions and more than 90% of adenocarcinomas. Recently, there has been a resurgence of the concept that foci of prostatic atrophy (referred to as proliferative inflammatory atrophy or PIA) may be precursor lesions for the development of prostate cancer and/or high-grade PIN. Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response. Because not all PIA cells are positive for GSTP1 protein, we hypothesized that some of the cells within these regions acquire GSTP1 CpG island hypermethylation, increasing the chance of progression to high-grade PIN and/or adenocarcinoma. Separate regions (n =199) from 27 formalin-fixed paraffin-embedded prostates were microdissected by laser-capture microdissection (Arcturus PixCell II). These regions included normal epithelium (n = 48), hyperplasticepithelium from benign prostatic hyperplasia nodules (n = 22), PIA (n = 64), high-grade PIN (n = 32), and adenocarcinoma (n = 33). Genomic DNA was isolated and assessed for GSTP1 CpG island hypermethylation by methylation-specific polymerase chain reaction. GSTP1 CpG island hypermethylation was not detected in normal epithelium (0 of 48) or in hyperplastic epithelium (0 of 22), but was found in 4 of 64 (6.3%) PIA lesions. The difference in the frequency of GSTP1 CpG island hypermethylation between normal or hyperplastic epithelium and PIA was statistically significant (P = 0.049). Similar to studies using nonmicrodissected cases, hypermethylation was found in 22 of 32 (68.8%) high-grade PIN lesions and in 30 of 33 (90.9%) adenocarcinoma lesions. Unlike normal or hyperplastic epithelium, GSTP1 CpG island hypermethylation can be detected in some PIA lesions. These data support the hypothesis that atrophic epithelium in a subset of PIA lesions may lead to high-grade PIN and/or adenocarcinoma. Because these atrophic lesions are so prevalent and extensive, even though only a small subset contains this somatic DNA alteration, the clinical impact may be substantial.
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PMID:Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. 1293 33


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