Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basal cells lining prostatic acini have unique morphologic and immunophenotypic characteristics. The role of these uncommitted cells in the genesis of cancer in the prostate is intriguing. Here, we discuss immunophenotypic and molecular features of basal cells of prostatic acini, and compare them with those of cytologically transformed cells of prostatic intraepithelial neoplasia (PIN) in both human tissues and animal models. Following a summary of the current concepts of molecular events in prostatic cancer, we will discuss the role of the ras-dependent pathway in early prostate carcinogenesis with a special emphasis on mitogen-activated protein kinase phosphatase (MKP-1). We will also outline the importance of techniques such as differential display-polymerase chain reaction (ddPCR) followed by in situ hybridization in the characterization of genes which may have a critical role in early prostate carcinogenesis. Finally, we will underscore the role of animal models in understanding the early events leading to neoplastic transformation of prostate cells.
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PMID:Molecular events in the early phases of prostate carcinogenesis. 887 97

Prostatic intraepithelial neoplasia (PIN) is considered as a precursor of prostate cancer and is frequently associated with it. Diagnosis of PIN on a prostate needle biopsy without associated carcinoma is a difficult problem since high-grade PIN does not necessarily mean that prostate cancer is always present and low-grade PIN is associated with cancer as well. Definition of parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN is of evident interest and we have reviewed our experience and recent data from the literature on this topic. High grade is a strong predictor of later cancer found on repeat biopsy (50-100%) and in these patients, serum prostate-specific antigen (PSA), digital rectal examination and transrectal ultrasound are predictors of later cancer found on repeat biopsy. High-grade PIN is, however, frequently associated with later cancer whatever PSA, even when < or = ng/ml. Low-grade PIN seems to behave like BPH since the incidence of later cancer is extremely low when PSA is < 4 ng/ml and is high when PSA > 10 ng/ml. Patients with high-grade PIN should systematically be rebiopsied after 3-6 months to exclude cancer because they are likely to have undiagnosed cancer. Patients with low-grade PIN and low PSA seem to have a low risk of later cancer found on repeat biopsy. Patients with low-grade PIN and high serum PSA should have repeat biopsies because the incidence of subsequent cancer is high and comparable to high-grade PIN. Further investigations are needed to optimize the management of patients with low-grade PIN and intermediate PSA level.
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PMID:Clinical prognostic criteria for later diagnosis of prostate carcinoma in patients with initial isolated prostatic intraepithelial neoplasia. 887 7

Biopsy or fine-needle aspiration cytology are the only appropriate methods for detection of prostatic intraepithelial neoplasia (PIN). PIN has been suggested to be a principal precursor of invasive carcinoma of the prostate. Most reports on an association of PIN and invasive prostatic cancer have a follow-up of less than 1 year, indicating that the successively diagnosed cancer most probably was present at the time of diagnosis of PIN. The natural history of PIN is unknown and detection of PIN should therefore not influence therapeutic decisions. If coexistent carcinoma is not found, close surveillance is recommended to identify a possible subsequent cancer at an early stage. Follow-up examinations should be performed at 6-month intervals for 2 years and thereafter annually.
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PMID:Follow-up of prostatic intraepithelial neoplasia. 887 8

The progression of prostatic intraepithelial neoplasia (PIN) to invasive prostate carcinoma has been analyzed in the C3(1)/T(AG) transgenic mouse model and appears very similar to the process proposed to occur in humans. PIN lesions in these transgenic mice histologically resemble those found in human PIN. Low-grade PIN was observed in the ventral and dorsolateral lobes at 2 months of age, whereas high-grade PIN was found in both lobes by 5 months of age. A progressive increase in the number of PIN lesions was observed with age. Prostate carcinomas, which appeared to arise from PIN lesions, were found by 7 months of age in the ventral lobe and 11 months of age in the dorsolateral lobe. Expression of T(AG) mRNA and protein in these lesions correlated with the development of PIN and carcinomas, as did the overexpression of p53 protein. Apoptosis levels were quite low in normal epithelial cells, moderate in low-grade PIN, and high in high-grade PIN and carcinomas. Levels of expression of proliferating cell nuclear antigen correlated with the degree of severity of the prostate lesions. Eighteen % of PIN lesions were found to already harbor Ha-ras mutations, whereas 33% of carcinomas showed various mutations in Ha-ras, Ki-ras, and/or p53. Mutations in Ha-ras may, therefore, be an early event in a significant portion of PIN lesions. Because high-grade PIN showed many characteristics similar to those observed in carcinomas and high-grade PIN was often found contiguous to carcinomas, we conclude that high-grade PIN is a precursor lesion of prostate carcinoma in this transgenic model. These transgenic mice will be useful to study mechanisms responsible for the progression of invasive carcinomas from PIN precursor lesions, as may occur during the development of prostate cancer in humans.
Cancer Res 1996 Nov 01
PMID:Progression of prostatic intraepithelial neoplasia to invasive carcinoma in C3(1)/SV40 large T antigen transgenic mice: histopathological and molecular biological alterations. 889 41

The Bcl-2 protein prolongs cell survival by overriding apoptosis. To explore the role of Bcl-2 in prostate tumorigenesis, immunoreactivity for Bcl-2 was examined in untreated and androgen-deprived tumours and lymph node metastasis. Following the transurethral resection, 150 untreated patients were maintained under surveillance until death or for a minimum of 11 years, and castration was performed at symptomatic progression. The Bcl-2 index (BI) was defined as the percentage of immunoreactive cells in a tumour. The mean BI was 12 in the untreated tumours, and BI was significantly higher in high-grade tumours, mean BI 17, than in low-grade tumours, mean BI 6. There was no correlation between BI and stage or metastatic disease, nor did BI predict cancer-specific survival. In 16 androgen-deprived, but non-relapsed tumours, the mean BI was 54, at a mean time of 22 months after castration, indicating a permanent increase of Bcl-2 protein expression after androgen withdrawal. In six patients, tissues from the prostate tumour and obturator lymph node metastasis were available. Four primary tumours immunostained for Bcl-2, but only one metastasis stained. Foci of highgrade prostatic intraepithelial neoplasia (PIN) were present in 44 of the 150 untreated tumours. All PIN foci were intensely immunoreactive for Bcl-2, and mean BI was 79, suggesting that Bcl-2 protein expression is associated with early prostate tumorigenesis.
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PMID:Bcl-2 immunoreactivity in prostate tumorigenesis in relation to prostatic intraepithelial neoplasia, grade, hormonal status, metastatic growth and survival. 893 Dec 89

We report the construction of a plasmid-based cDNA library made from microdissected cells derived from prostatic intraepithelial neoplasia. Total RNA was extracted and converted to blunt-ended, double-stranded cDNA by oligo(dT)-mediated reverse transcription followed by linker addition. A linker-specific primer with UDG-compatible ends was used to amplify the cDNA and the resulting PCR product was subcloned. A total of 154 clones were sequenced and results indicated that 81.5% of the clones derived from either known genes, anonymous expressed sequence tags, or novel transcripts with very little redundancy of screened clones. These results demonstrate the feasibility of constructing complex representative cDNA libraries from specific microdissected cell populations that represent microscopic precursor stages of cancer progression. This method should facilitate identification of transcripts specifically expressed in cells of a distinct histological origin and tumorigenic stage.
Cancer Res 1996 Dec 01
PMID:Construction of a representative cDNA library from prostatic intraepithelial neoplasia. 896 89

The role of c-myc in prostatic carcinogenesis is poorly understood. The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is not well-defined. We used fluorescence in situ hybridization (FISH) with a region-specific probe for c-myc (band 8q24) and chromosome enumeration probes for chromosomes 7, 8, 10, 12, and Y to evaluate genetic changes in matched PIN (48 foci), localized prostatic carcinoma (71 foci), and lymph node metastases (23 foci) in 25 totally embedded whole-mount stage D1 (T2-3 N1-3 M0) radical prostatectomy and pelvic lymphadenectomy specimens. The c-myc protein expression in these lesions was evaluated by immunohistochemistry. Foci with extra copies of c-myc could be divided into three groups: (a) those with simple gain of a whole chromosome 8 (no increase in c-myc copy number relative to the chromosome 8 centromere), which was identified in 42, 25, and 46% of foci of PIN, carcinoma, and metastases, respectively; (b) those with an intermediate increase in c-myc copy number relative to the chromosome 8 centromere, which was found in 8, 11, and 25% of foci of PIN, carcinoma, and metastases, respectively; and (c) those with substantial amplification of c-myc (large increases in c-myc copy number relative to the chromosome 8 centromere), which was detected in 0, 8, and 21% of foci of PIN, carcinoma, and metastases, respectively. Substantial amplification of c-myc was strongly correlated with increasing cancer nuclear grade and immunohistochemical evidence of c-myc protein overexpression. Numeric chromosomal anomalies were found in 67, 68, and 96% of foci of PIN, carcinoma, and metastases, respectively. The most frequent anomaly in PIN and carcinoma was a gain of chromosome 8, and the presence of this anomaly strongly correlated with Gleason score. Carcinoma foci usually contained more FISH anomalies than paired PIN foci, but three prostates contained one or more PIN foci with more anomalies than carcinoma. Thirteen primary tumor foci exhibited intratumor genetic heterogeneity by FISH. One or more foci of the primary tumor usually shared FISH anomalies with the matched metastases. Our FISH results indicate that: (a) gain of chromosome 8 and amplification of c-myc are potential markers of prostate carcinoma progression; (b) PIN is likely a precursor of carcinoma; (c) intraglandular and intratumoral genetic heterogeneity is relatively common; and (d) usually a single focus of cancer gives rise to metastases.
Cancer Res 1997 Feb 01
PMID:Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. 901 85

High-grade prostatic intraepithelial neoplasia (PIN) is considered the most likely precursor of invasive prostatic adenocarcinoma, and is characterized by cellular proliferations within preexisting ducts and glands with cytological changes mimicking cancer. The extent and multicentricity of this clinically important histopathologic lesion have not been fully defined. We sought to determine whether the extent and zonal distribution of PIN are related to prostate cancer. A total of 195 whole-mounted radical prostatectomy specimens were evaluated. All patients had clinically localized cancer, and none had received preoperative therapy. The zonal location and multicentricity of PIN were recorded, and the volume of PIN was measured using a grid-counting method according to pattern (tufting, micropapillary, cribriform, and flat) and spatial proximity to cancer (less than or equal to 2 mm from cancer, and greater than 2 mm from cancer). The results were correlated with patient age, prostate volume, cancer volume, pathological stage, and Gleason grade. High-grade PIN was identified in 86% of cases, usually with multiple architectural patterns of PIN in each positive case: tufting (97% of cases), micropapillary (66% of cases), cribriform (19% of cases), and flat (21% of cases). The mean volume of PIN was 1.32 cm3 (standard error [SE], 0.10; range, 0 to 8.12 cm3), and was greater for PIN within 2 mm of cancer (mean, 1.0 cm3) than for PIN more than 2 mm from cancer (mean, 0.3 cm3). PIN was usually multicentric (64.5% of cases) and located in the nontransition zone (63%) or all zones (36%) of the prostate. There was a positive correlation of total volume of PIN and volume of cancer, but this correlation was significant only for PIN within 2 mm of cancer. The volume of PIN was positively correlated with age, pathological stage, and Gleason score; most of these positive correlations were caused by PIN within 2 mm of cancer rather than that greater than 2 mm from cancer. Our results indicate that the extent and zonal distribution of high-grade PIN and carcinoma are strongly associated, and that PIN is frequently multicentric. This supports the hypothesis that PIN is a premalignant lesion.
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PMID:The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. 902 93

Quantifiable, well-characterized cancer risk factors demonstrate the need for chemoprevention and define cohorts for chemopreventive intervention. For chemoprevention, the important cancer risk factors are those that can be measured quantitatively in the subject at risk. These factors, called risk biomarkers, can be used to identify cohorts for chemoprevention. Those modulated by chemopreventive agents may also be used as endpoints in chemoprevention studies. Generally, the risk biomarkers fit into categories based on those previously defined by Hulka: 1) carcinogen exposure, 2) carcinogen exposure/effect, 3) genetic predisposition, 4) intermediate biomarkers of cancer, and 5) previous cancers. Besides their use in characterizing cohorts for chemoprevention trials, some risk biomarkers can be modulated by chemopreventive agents. These biomarkers may be suitable surrogate endpoints for cancer incidence in chemoprevention intervention trials. The criteria for risk biomarkers defining cohorts and serving as endpoints are the same, except that those defining cohorts are not necessarily modulated by chemopreventive agents. A primary criterion is that the biomarkers fit expected biological mechanisms of early carcinogenesis-i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, and short latency compared with cancer. They must occur in sufficient number to allow their biological and statistical evaluation. Further, the biomarkers should be assayed reliably and quantitatively, measured easily, and correlated to cancer incidence. Particularly important for cancer risk screening in normal subjects is the ability to use noninvasive techniques that are highly specific, sensitive, and quantitative. Since carcinogenesis is a multipath process, single biomarkers are difficult to correlate to cancer, as they may appear on only one or a few of the many possible causal pathways. As shown in colorectal carcinogenesis, the risks associated with the presence of biomarkers may be additive or synergistic. That is, the accumulation of genetic lesions is the more important determinant of colorectal cancer compared with the presence of any single lesion. Thus, batteries of biomarker abnormalities, particularly those representing the range of carcinogenesis pathways, may prove more useful than single biomarkers both in characterizing cohorts at risk and defining modulatable risks. Risk biomarkers are already being integrated into many chemoprevention intervention trials. One example is the phase II trial of oltipraz inhibition of carcinogen-DNA adducts in a Chinese population exposed to aflatoxin B1. Also, urine samples from subjects in this trial will be screened for the effect of oltipraz on urinary mutagens. A second example is a chemoprevention protocol developed for patients at high risk for breast cancer; the cohort is defined both by hereditary risk and the presence of biomarker abnormalities. Modulation of the biomarker abnormalities is a proposed endpoint. Also, dysplastic lesions, such as prostatic intraepithelial neoplasia, oral leukoplakia and colorectal adenomas, have been used to define high-risk cohorts and as potential modulatable surrogate endpoints in chemoprevention trials.
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PMID:Risk biomarkers and current strategies for cancer chemoprevention. 902 92

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
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PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95


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