Kinetic profiles of intraepithelial and invasive prostatic neoplasias: the key role of down-regulated apoptosis in tumor progression (original) (raw)
Related papers
New relationships between prostatic intraepithelial neoplasia and prostatic carcinoma
Journal of Cellular Biochemistry, 1992
Our group has been studying the progressive molecular changes in prostatic epithelium which precede the invasive phenotype. Initial studies revealed similar alterations in cytoskeletal proteins between high grade prostatic intraepithelial neoplasia (PIN) lesions and invasive carcinoma. Specifically we observed an increased expression of certain cytokeratins and decreased expression of vimentin. We also noted a change in glycosylation as detected by Ulex europaeus staining. Using the latter technique we were able to microdissect and isolate nuclei from areas of low and high grade PIN lesions as well as from invasive carcinoma for morphometric analysis. Similarities in nuclear size, chromatin heterogeneity, and nuclear DNAcontent between low and high grade PIN and invasive carcinoma in carcinomatous specimens were noted. In contrast, these parameterswere significantly different in lowgrade PIN lesionsobtained from benign prostatic transurethral resection (TURP) specimens. In addition, DNA histograms revealed similar proliferative indices between high grade PIN and invasive carcinoma, which differed significantly from low grade PIN. Parameters thought to be relative to the invasive phenotype were also examined, such as the members of the rnetalloproteinase family; although normal luminal cells fail to express detectable levels of these enzymes, invasive carcinoma and even low grade PIN lesions express both the 72 kDa and 92 kDa type IV collagenase. Taken together, these data indicate that the dysplastic cells of PIN lesions and carcinomas are similar in nuclear and genomic features as well as protease expression. Our current working hypothesis is that these cells are already armed with the necessary proteases to invade the basal lamina but in an inactive form. Tumor progression requires an additional event of protease activation.
Cancer Research, 2004
To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 do...
Prostatic carcinogenesis: More insights
Journal of Microscopy and Ultrastructure, 2017
IntroductIon Prostatic carcinoma is a major health problem as it is considered the second most common malignancy among men and the fifth leading cause of cancer-related death worldwide. [1,2] It results from a combination of genetic and environmental factors that alter key cellular processes and involves multiple cellular pathways and molecules implicated in its initiation and progression, however, the specific underlying mechanisms of prostatic carcinogenesis are still unrevealed. [3,4] Maspin (mammary serine protease inhibitor) and prohibitin (PHB) are important key molecules involved in different cellular mechanisms related to carcinogenesis. Maspin is a member of the serine protease inhibitor/noninhibitor superfamily (serpin), located on chromosome 18q21.3-q23. Interestingly, it was described to be overexpressed in some cancers including pancreatic, gallbladder, colorectal, and thyroid cancers, while downregulated in other cancers including breast and gastric carcinomas as well as melanomas. [5,6] PHB is a high molecular weight protein located in the mitochondria, nucleus, and plasma membranes [7] and has been described to be involved in multiple processes controlling the development and growth of different organ cancers. Similar to maspin, PHB overexpression was described in some cancers involving the cervix, esophagus, stomach, breast, lung, bladder, thyroid, and ovary, while others such as gliomas showed downregulation. [8] Aim of the work This work was designed to study the immunohistochemical expression of maspin and PHB in prostatic carcinoma in comparison to their expression in benign prostatic hyperplasia (BPH) to give more insights about their roles in prostatic carcinogenesis. materIals and methods This study was carried out on paraffin blocks of formalin-fixed tissue sections of 45 prostatic specimens including 30 cases Background: Prostatic carcinoma ranks as the second most common malignant tumor and the fifth cause of cancer-related deaths in men. Many studies now focus on the different molecules involved in prostatic carcinogenesis. Maspin and prohibitin (PHB) are suggested to play crucial roles in the development and progression of many cancers; however, their roles in prostatic carcinogenesis have not been fully elucidated. Aim: This work was designed to study the immunohistochemical expression of maspin and PHB in prostatic carcinoma in comparison to their expression in benign prostatic hyperplasia (BPH) to give more insights about their roles in prostatic carcinogenesis. Materials and Methods: Archival blocks of 30 cases of prostatic adenocarcinomas and 15 cases of BPH were subjected to histopathological examination and immunohistochemical evaluation of maspin and PHB expression. Results: Maspin showed higher expression in prostatic carcinoma (88.9% of cases) compared to BPH (20% of cases). PHB expression was detected only in prostatic carcinoma (84.4% of cases), while all cases of BPH were negative. The expression of both maspin and PHB showed statistically significant increase with increasing Gleason score (P = 0.0125 and 0.0065 respectively). Conclusions: Overexpression of maspin and PHB in prostatic carcinoma reflects their vital roles in prostatic carcinogenesis. Their upregulation with increasing Gleason score indicates their prognostic significance. Moreover, PHB may differentiate between prostatic carcinoma and BPH being expressed only by malignant cells.
Urology, 2000
Objectives. To validate with an independent study that simple atrophy/postatrophic hyperplastic lesions (proliferative inflammatory atrophy [PIA]) often merge directly with high-grade prostatic intraepithelial neoplasia (PIN). Methods. Using radical prostatectomies (n ϭ14), all high-grade PIN and adenocarcinoma lesions were identified. We examined the two-dimensional topographic relationship between individual high-grade PIN lesions and PIA, between carcinoma lesions and PIA, and between carcinoma lesions and high-grade PIN. To reduce the possibility that high-grade PIN lesions represented intraprostatic dissemination of carcinoma, all specimens contained total carcinoma volumes of less than 0.5 cc. Results. High-grade PIN merged with PIA in 267 (42.5% of high-grade PIN lesions) of 629 lesions, was adjacent in 57 lesions (9%), was near in 233 lesions (37%), and was distant from PIA in 72 lesions (11.5%). Carcinoma did not merge with PIA; it was adjacent in 24 (30.4%) of 79 lesions, was near in 46 lesions (58.2%), and was distant from PIA in 9 lesions (11.4%). Of 79 carcinoma lesions, 18 (23%) merged with high-grade PIN, 11 (14%) were adjacent, 26 (33%) were near, and 24 (30%) were distant from high-grade PIN. Areas of presumed low-grade PIN were often found in association with high-grade PIN and PIA. Conclusions. Morphologic transitions between high-grade PIN and PIA occur frequently. Although the mere topographic relation of the lesions is not definitive proof of a continuum, these results are consistent with a model in which the proliferative epithelium in PIA may progress to PIN and/or adenocarcinoma.
Image Analysis & Stereology, 2011
High-grade prostate intraepithelial neoplasia (PIN) is considered a precursor of prostate adenocarcinoma. The aim of this study was to quantitate the differences between basal and luminal cells of PIN in relation to mean nuclear volume (νVnuc), and proliferating cell nuclear antigen labeling index (LIPCNA), and to compare these estimates with those obtained in normal prostate and carcinoma. The epithelium of both normal and PIN specimens was segmented in basal and luminal compartments, and the νVnuc and LIPCNA measured in both strata. νVnuc was significantly lower in normal epithelium than in both PIN and carcinoma. The νVnuc of basal layer of PIN was significantly higher than in luminal stratum. The luminal νVnuc was similar in both PIN and adenocarcinoma. The LIPCNA was greater in PIN and adenocarcinoma than in normal glands. The LIPCNA of basal cells from PIN was similar to that observed in the basal stratum from normal prostate, whereas the luminal proliferation from PIN was sim...
2005
Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. This one year Exploration-Hypothesis Development Award is aimed to identify the possible molecular markers to predict the malignant tendency of the Prostate Intraepthelial Neoplasia (PIN) lesion. During the past year, our main effort has been made to establish reliable methods to micro-dissect the PIN cells, to extract RNA, and to use this RNA to perform microquantity differential display to analyze the differential expression patterns between the cancer precursor PINs and the benign PIN lesions. Altogether, we have assessed about 5000 functional genes and found 53 differentially-expressed bands. With the limited time schedule, we have tried to recover 11 genes and successfully obtained 7 sequences. We have examined the expression status of these 7 candidates in a large number of PINs and in an archival set of prostate tissues. While continue to assess their potential of predicting malignant tendency of PINs, we have also found that one of them (osteopontin) is an important prognostic factor for prostate cancer.
Oncology Reports, 2006
In order to evaluate the molecular heterogeneity of prostate cancer, this study examined the expression of Aktpathway related parameters within the cancerous prostate gland. PTEN, p-Akt and p27 kip1 are known to be altered in prostate cancer. Tissue samples from malignant, tumor adjacent benign and benign areas of 25 whole mounted prostate cancer specimens were processed to 583 tissue microarray cores. Immunohistochemically determined biomarker expression was correlated to the different localizations. p-Akt and p27 kip1 showed increased staining in malignant tissue compared to the respective benign tissue (p<0.01 and p<0.05). The adjacent but histologically benign tissue had increased levels (p<0.05 and p<0.01), whereas no significant difference was found between the adjacent and malignant regions. A highly significant correlation of p-Akt and p27 kip1 in benign tissue (p<0.001) was lost in the adjacent areas and in the malignant tissue (p=0.054 and p=0.12). In tendency, PTEN expression was decreased in the malignant regions and revealed the highest staining in the adjacent zone. According to the results obtained, the expression of p-Akt and p27 kip1 was increased in both the adjacent microscopically benign tissue as well as the primary tumors when compared with the histologically benign tissue specimens that served as biological control. The increased expression of PTEN indicates its regulatory function in the initial steps of a deteriorated cell cycle control as well as uncontrolled cellular proliferation, for example, which seem to be present in the normal prostatic tissue surrounding the primary malignant lesion. The addition of molecular markers to a 'classical' histopathological approach might contribute to an enhanced sensitivity of analytical approaches aimed at the detection of malignant or premalignant lesions within prostatic biopsies.
Turkish Journal of Pathology
Objective: Deviations in the apoptotic process have been demonstrated in prostate carcinogenesis. We aimed to evaluate especially the process of extrinsic apoptosis in the spectrum of neoplastic lesions of the prostate epithelium so as to reveal the variations in the apoptotic process. Material and Method: The study included 20 benign prostatic hyperplasia, 8 high-grade prostatic intraepithelial neoplasia and 82 prostatic carcinoma patients. Immunohistochemistry was performed on sections obtained from materials of suprapubic prostatectomy, tru-cut biopsy, transurethral resection and radical prostatectomy. While Fas and FasL were evaluated in glandular and stromal areas, Dcr1 and FLIP were evaluated in only glandular areas. Intensity and extent of immunostaining for Fas and FasL antibodies were separately scored and both scores were summarized. The total score of ≥ 4 both for Fas and FasL, expressions of FLIP and Dcr1determined in more than 5% of glandular areas were accepted as positive. Results: Glandular FasL positivity was observed in 63.8 and 20% of the cases with prostatic carcinoma and benign prostatic hyperplasia, respectively (p=0.001). The loss of stromal Fas expression in PCa was obvious (p<0.001). FLIP positivity was more frequently seen in high-grade prostatic intraepithelial neoplasia and PCa. Conclusion: In prostatic carcinoma, decreased stromal Fas expression, contrary to higher glandular FasL positivity, supports the assertion that sensitivity of epithelial and stromal cells to apoptosis and their protective pathways against apoptosis undergo alterations. Increased FLIP expressions in high-grade prostatic intraepithelial neoplasia and prostatic carcinoma can also be interpreted accordingly.
Proliferative Tumor Doubling Times of Prostatic Carcinoma
Prostate Cancer, 2011
Prostate cancer (PCa) has a variable biology ranging from latent cancer to extremely aggressive tumors. Proliferative activities of cancers may indicate their biological potential. A flow cytometric assay to calculate maximum proliferative doubling times (T max ) of PCa in radical prostatectomy specimens after preoperative in vivo bromodeoxyuridine (BrdU) infusion is presented. Only 4/17 specimens had tumors large enough for flow cytometric analysis. The T max of tumors was similar and ranged from 0.6 to 3.6 months. Tumors had calculated doubling times 2-to 25-fold faster than their matched normal tissue. Variations in labeling index and T max were observed within a tumor as well as between different Gleason grades. The observed PSA doubling times (PSA-DT) ranged from 18.4 to 32.0 months, considerably slower than the corresponding T max of tumors involved. While lack of data for apoptotic rates is a limitation, apparent biological differences between latent versus aggressive PCa may be attributable to variations in apoptotic rates of these tumors rather than their cell proliferative rates.