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Results for “Proliferation”

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PubMed1993

Cell proliferation kinetics in acetic acid-induced gastric ulcer evaluated by immunohistochemical staining of proliferating cell nuclear antigen.

A monoclonal antibody to proliferating cell nuclear antigen (PCNA) has been previously shown to be capable of identifying proliferating cells. We investigated proliferative activity in the healing process of acetic acid-induced gastric ulcer by immunohistochemical staining of PCNA and 5-bromo-2-deoxyuridine (BrdU), and the two methods were compared. Cell proliferative activity of regenerated mucosa around ulcers showed continuous acceleration for 42 days, and PCNA-labeled cells had stained nuclei as clearly discernible as those of BrdU-labeled cells. In addition, immunohistochemical staining of PCNA provided reproducible and quantifiable results without the requirement of pretreatment. We conclude that immunohistochemical staining of PCNA may represent a useful technique for analysis of proliferative activity during healing of gastric ulcers.

Acetates↗

PubMed1994

Expression of proliferation-associated proteins (proliferating cell nuclear antigen and Ki-67 antigen) in Bowen's disease.

Bowen's disease and invasive squamous cell carcinoma arising in Bowen's disease (Bowen's carcinoma) were investigated immunohistochemically with regard to their expression of proliferating cell nuclear antigen (PCNA) and the Ki-67 antigen. Both proliferation-associated proteins were found in all layers of the tumours, and were present in nuclei of any size and shape. The nucleoli lacked PCNA immunoreactivity, but they expressed the Ki-67 antigen. The PCNA labelling index was 36.9 +/- 12.6% in Bowen's disease (n = 16), and 40.7 +/- 11.0% in Bowen's carcinoma (n = 3). The Ki-67 antigen labelling index was 43.6 +/- 16.7% in Bowen's disease (n = 16), and 51.7 +/- 11.6% in Bowen's carcinoma (n = 3). Dyskeratotic cells were positive for PCNA and the Ki-67 antigen, suggesting that these cells are not in a post-mitotic state. We conclude that in dyskeratotic cells of Bowen's disease the cell cycle is interrupted by nuclear disorganization.

Antigens, Neoplasm↗

PubMed2000

Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators.

Peroxisome proliferators (PPs) are a large class of structurally dissimilar chemicals that have diverse effects in rodents and humans. Most, if not all, of the diverse effects of PPs are mediated by three members of the nuclear receptor superfamily called peroxisome proliferator-activated receptors (PPARs). In this review, we define the molecular mechanisms of PPs, including PPAR binding specificity, alteration of gene expression through binding to DNA response elements, and cross talk with other signaling pathways. We discuss the roles of PPARs in growth promotion in rodent hepatocarcinogenesis and potential therapeutic effects, including suppression of cancer growth and inflammation.

Animals↗

PubMed2005

Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells.

PURPOSE: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator-activated receptor (PPAR) gamma-mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ERalpha and PPARgamma pathways in breast cancer cells. EXPERIMENTAL DESIGN: Using MCF7 and HeLa cells as model systems, we did transient transfections and electrophoretic mobility shift assay and chromatin immunoprecipitation studies to evaluate the ability of ERalpha to influence PPAR response element-mediated transcription. A possible direct interaction between ERalpha and PPARgamma was ascertained by co-immunoprecipitation assay, whereas their modulatory role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway was evaluated by determining PI3K activity and AKT phosphorylation. As a biological counterpart, we investigated the growth response to the cognate ligands of both receptors in hormone-dependent MCF7 breast cancer cells. RESULTS: Our data show for the first time that ERalpha binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ERalpha and PPARgamma, which also involve the p85 regulatory subunit of PI3K. Interestingly, ERalpha and PPARgamma pathways have an opposite effect on the regulation of the PI3K/AKT transduction cascade, explaining, at least in part, the divergent response exerted by the cognate ligands 17beta-estradiol and BRL49653 on MCF7 cell proliferation. CONCLUSION: ERalpha physically associates with PPARgamma and functionally interferes with PPARgamma signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.

Breast Neoplasms↗

PubMed2005

Peroxisome proliferator-activated receptor-gamma agonists suppress adrenocortical tumor cell proliferation and induce differentiation.

CONTEXT: Thiazolidinediones (TZDs) have been implemented into clinical practice for the treatment of type 2 diabetes mellitus as specific peroxisome proliferator-activated receptor (PPAR)-gamma ligands. Moreover, recent evidence has suggested that TZDs might have favorable effects in the treatment of a variety of tumors as differentiation-inducing agents. Adrenocortical carcinoma (ACC) is a rare tumor entity with poor prognosis due to its highly malignant phenotype and lack of effective treatment options. OBJECTIVE: The purpose of this study was to investigate effects of TZDs on adrenocortical cancer cells. RESULTS: PPARgamma mRNA expression was detectable in all adrenocortical tumors including ACCs at similar levels. Furthermore, incubation of the adrenocortical tumor cell line NCI h295 with the PPARgamma agonist rosiglitazone led to a decrease in cell viability, a decrease of cellular proliferation, and an increase in apoptosis as well as steroidogenesis. On the molecular level, NCI h295 cells expressed higher levels of ACTH receptor (melanocortin receptor-2) mRNA upon treatment, whereas cyclin E mRNA was reduced, thus reflecting a shift toward an expression pattern found in less aggressive adrenocortical tumors in vivo. Accordingly, luciferase experiments confirmed an increased promoter activity for the melanocortin receptor-2 after stimulation with rosiglitazone. Coincubation with the specific PPARgamma antagonist GW9662 demonstrated the inhibition of TZD-induced increase in steroidogenesis, whereas growth suppression upon TZD treatment was not affected by GW9662. CONCLUSIONS: Thus, both PPARgamma-dependent and PPARgamma-independent effects of TZD treatment are likely to contribute to the observed phenotypical effects on NCI h295 cells. Taken together, these data indicate that TZDs might have the potential to become an additional treatment option as differentiation-inducing agents in patients with ACC.

Adrenal Cortex Neoplasms↗

PubMed2001

Reactivity of anti-proliferating cell nuclear antigen (PCNA) murine monoclonal antibodies and human autoantibodies to the PCNA multiprotein complexes involved in cell proliferation.

Proliferating cell nuclear Ag (PCNA) occurs as a component of multiprotein complexes during cell proliferation. We found the complexes to react with murine anti-PCNA mAbs, but not with anti-PCNA Abs in lupus sera. The complexes were purified from rabbit thymus extract by affinity chromatography using anti-PCNA mAbs (TOB7, TO17, and TO30) and analyzed by ELISA, immunoprecipitation, immunoblotting, and HPLC gel filtration. That PCNA was complexed with other proteins was demonstrated by its copurification with a group of proteins excluded by an HPLC G3000 SW column. Although immunoblot analysis showed the mAbs to react exclusively with the 34-kDa PCNA polypeptide, they nonetheless immunoprecipitated the same group of proteins, confirming the interaction of the isolated PCNA with other proteins. Anti-PCNA sera, including AK, which reacts with biologically functional sites on PCNA, did not react with complexed PCNA, but did react with it once it was dissociated from the complexes. PCNA complexes in turn reacted with murine anti-DNA mAbs, as well as with Abs against p21, replication protein A, DNA helicase II, cyclin-dependent kinases 4 and 5, and topoisomerase I. These findings suggest that the PCNA complexes purified using anti-PCNA mAbs comprise the "protein machinery" for DNA replication and cell cycle regulation. They also suggest that anti-PCNA mAbs are useful tools with which to characterize the protein-protein interactions within PCNA complexes, as well as the autoimmune responses to proteins interacting with PCNA, which may shed light on the mechanisms of autoantibody production in lupus patients.

Animals↗

PubMed1999

Addition of peroxisome proliferator-activated receptor alpha to guinea pig hepatocytes confers increased responsiveness to peroxisome proliferators.

The fibrate drugs, such as nafenopin and fenofibrate, show efficacy in hyperlipidemias but cause peroxisome proliferation and liver tumors in rats and mice via nongenotoxic mechanisms. However, humans and guinea pigs appear refractory to these adverse effects. The peroxisome proliferator (PP)-activated receptor alpha (PPAR alpha) mediates the effects of PPs by heterodimerizing with the retinoid X receptor (RXR) to bind to DNA at PP response elements (PPREs) upstream of PP-regulated genes, such as acyl-CoA oxidase. Hepatic expression of PPAR alpha in guinea pigs and humans is low, suggesting that species differences in response to PPs may be due at least in part to quantity of PPAR alpha. To test this hypothesis, we introduced mouse PPAR alpha and its heterodimerization partner, RXR alpha, into guinea pig hepatocytes by transient transfection and determined responsiveness to the PP nafenopin by cyanide-insensitive palmitoyl-CoA oxidation (CIPCO). Expression of the mRNA for mouse PPAR alpha in transfected guinea pig hepatocytes was verified using species-specific PCR. In guinea pig hepatocytes transfected with control plasmids and treated with 50 microM nafenopin in the absence or presence of the RXR ligand, 9-cis-retinoic acid (5 microM) gave only a 1.7 +/- 1.5- or 3.3 +/- 1.5-fold induction in CIPCO, respectively. However, addition of ligands to hepatocytes co-transfected with both mPPAR alpha and RXR gave a strong induction of CIPCO (14.8 +/- 8.6-fold). Mouse, human, and guinea pig PPAR alpha showed equivalent function in the CIPCO assays. Thus, quantity of PPAR alpha plays a significant role in the lack of response to PPs in guinea pigs. In humans, however, lack of PPAR alpha may be only one factor dictating lack of response because recent data show that the human acyl-CoA oxidase gene lacks a functional PP response element.

Alitretinoin↗

PubMed1992

Analysis of proliferating hepatocytes using a monoclonal antibody against proliferating cell nuclear antigen/cyclin in embedded tissues from various liver diseases fixed in formaldehyde.

The authors studied histochemically the morphologic features of proliferating hepatocytes positive for proliferating cell nuclear antigen (PCNA/cyclin) to analyze the process of liver regeneration in embedded tissues fixed with formaldehyde using an anti-PCNA/cyclin monoclonal antibody. In liver specimens from patients with acute viral hepatitis (AVH) and confluent necrosis, many small basophilic hepatocytes surrounding large clear hepatocytes were positively stained in the areas next to the confluent necrosis. Therefore these small hepatocytes may be daughter cells derived from large clear hepatocytes that probably enter the mitotic cell cycle repeatedly to repair a large necrotic area. In the case of AVH with spotty necrosis, the positively stained hepatocytes were scattered around the necrotic foci. In the liver specimens from patients with chronic active hepatitis, most of the positively stained hepatocytes were located next to the necrotic area. As for cirrhosis of the liver, the number of hepatocytes positive for PCNA/cyclin varied greatly in different pseudolobules, and in the specimens of hepatocellular carcinoma (HCC), the HCC cells positive for PCNA/cyclin were detected throughout the cancer nests.

Antibodies, Monoclonal↗

PubMedDate not supplied

Prognostic value of cell proliferation in breast cancer as determined by proliferating cell nuclear antigen (PCNA) immunostaining.

A series of 175 biopsies from primary tumours were subjected to immunostaining for proliferation cell nuclear antigen (PCNA) and histopathological analysis for prognostic factors in 175 women with breast cancer followed up for nine years. In normal breast epithelium, only occasional nuclei were positive for PCNA. In breast carcinomas, the fraction of nuclei positive for PCNA showed considerable intratumoural variation, usually being highest at the invasive tumour margins. The fraction of positive nuclei was significantly related to histological grade (p less than 0.001), histological type (p = 0.049) and tumor recurrence (p = 0.01). The fraction of positive nuclei predicted recurrence-free survival (p = 0.007) and overall survival (p = 0.0158) in univariate analysis. In the multivariate analysis including also the standard prognostic factors, the PCNA positivity predicted recurrence-free survival (p = 0.004) and overall survival (p = 0.030) independently. The results show that the light microscopic assessment of the growth fraction as determined by PCNA immunolabeling has independent prognostic value in breast carcinomas like some other (e.g. S phase fraction, mitotic index, Ki-67) previously characterized proliferation indices.

Adult↗

PubMed2003

Comprehensive gene expression analysis of peroxisome proliferator-treated immortalized hepatocytes: identification of peroxisome proliferator-activated receptor alpha-dependent growth regulatory genes.

Chemicals known as peroxisome proliferators (PPs) are the subject of intense study because of their ability to cause hepatocellular carcinoma in laboratory rodents. These chemicals act through a family of proteins termed the peroxisome proliferator-activated receptors (PPARs), in particular PPARalpha. It has become increasingly apparent that the role of the PPs in the development of cancer encompasses many different aspects of cell growth regulation. Immortalized hepatocytes from wild-type (PPARalpha(+/+)) and PPARalpha(-/-) mice were generated using a temperature-sensitive SV40 virus. Characterization of the murine SV40 hepatocytes (MuSH) generated from both genotypes (MuSHalpha(+/+), MuSHalpha(-/-)) show markers of differentiation such as albumin expression, but is devoid of Kupffer cell contamination. Hallmark PPARalpha-mediated responses such as induction of acyl-CoA oxidase mRNA by PPs are present in the MuSHalpha(+/+) but are absent in MuSHalpha(-/-) cells. In contrast to most cell culture systems, the wild-type MuSH hepatocytes retain the mitogenic activity of PPs, whereas the MuSHalpha(-/-) does not respond in this manner, thus making this cell culture system an ideal tool to examine growth regulatory gene expression affected by PPs. Microarray experiments performed on both cell types identified many genes in which regulation is dependent on the presence of PPARalpha, and these changes were verified with reverse transcriptase-PCR. Genes involved in carcinogenesis and control of the cell cycle that are regulated by PPs in a PPARalpha-dependent manner include ubiquitin COOH-terminal hydrolase 37 (also known as UCT-L5) and cyclin T1. These results show that MuSH cells reflect the biological properties of both the wild-type and PPARalpha-null animals and can be used to identify novel PPARalpha-regulated genes that could be involved in regulation of the cell cycle and carcinogenesis.

Animals↗

PubMed2001

Expression of proliferating cell associated protein, Ki-67, supports cellular proliferation in WHO Class IV lupus nephritis.

Ki-67 expression in diffuse proliferative lupus nephritis, WHO Class IV, was compared against normal controls to establish that cellular proliferation is involved in the production of glomerular hypercellularity. Twenty-three histologically confirmed WHO Class IV lupus nephritis and 23 normal control renal tissue were immunohistochemically stained with a polyclonal antibody to Ki-67 (Dako) using the peroxidase labelled streptavidin bioitin kit (Dako). There were 20 females and 3 males, with 17 Chinese and 6 Malays in the WHO Class IV lupus nephritis group. Ages of patients ranged between 10-56 years with a mean of 31.9 years. The normal controls, 20 males and 3 females, and ethnically 9 Indians, 7 Malays, 2 Chinese, and 5 foreign nationals (4 Indonesians and 1 Bangladeshi), had an age range between 15-33 years (mean = 23.3 years). Sixteen (69.6%) WHO Class IV lupus nephritis and 8 (34.8%) normal controls demonstrated Ki-67 immunoreactivity in at least 1 glomerulus (p<0.05). Of the 256 WHO Class IV lupus nephritis non-sclerosed, glomeruli studied, 37 (14.5%) were Ki-67 immunopositive compared with normal controls where 16 (0.7%) of 2159 glomeruli demonstrated Ki-67 (p< 0.01). Cellular proliferative activity, as evidenced by Ki-67 expression, was significantly increased in WHO Class IV lupus nephritis confirming that cell proliferation contributes to glomerular hypercellularity.

Adolescent↗

PubMed1994

Sources of variation in the assessment of cell proliferation using proliferating cell nuclear antigen immunohistochemistry.

The reproducibility in quantitation of proliferation activity, determined using the monoclonal antibody 19A2 to proliferating cell nuclear antigen (PCNA), was tested in visual and computer-assisted analyses of brain tumor material. The PCNA labeling index was scored using count (PCNA-LI, visual and computer analyses) and area (PCNA-LIa, computer analysis) estimates of immunopositivity. The quality of immunostaining was the most important reason for variation in the assessment results. Other significant variation sources in the assessment were experience in selecting microscopic fields and distinguishing immunopositive nuclei from immunonegative ones. Computer-assisted analysis improved the reproducibility of quantitation between different observers (visual rPCNA-LI = 0.624 versus computer assisted rPCNA-LI = 0.904). Also, the use of PCNA-LIa improved the intraobserver and interobserver reproducibility in different stainings (observer 1:rPCNA-LI = 0.857 versus rPCNA-LIa = 0.874; observers 1 and 2: rPCNA-LI = 0.904 versus rPCNA-LIa = 0.927; observers 3 and 4: rPCNA-LI = 0.848 versus rPCNA-LIa = 0.906). PCNA-LIa by computerized image analysis improves accuracy in the evaluation of the granularly expressed PCNA level. Furthermore, the effect of tumor heterogeneity on the assessment results can be diminished with the computerized method because large tissue areas can be analyzed faster.

Astrocytoma↗

PubMed1995

Optimization of immunohistochemical staining of proliferating cells in paraffin sections of breast carcinoma using antibodies to proliferating cell nuclear antigen and the Ki-67 antigen.

Antibodies to proliferating cell nuclear antigen (PCNA) and the MIB-1 antibody to the Ki-67 antigen were titrated to optimize identification of proliferating cells in formalin-fixed paraffin-embedded tissue from a series of 40 human breast carcinomas. Cell culture studies have previously demonstrated that immunostaining for both PCNA and the Ki-67 antigen produces strong granular nuclear staining during S phase. PC10, other anti-PCNA antibodies (PC2, PC5, PC8 and 19F4) and MIB-1 were used at the minimum dilution which allowed a clear distinction between cells with strong and weak staining. With the anti-PCNA antibodies, nickel-cobalt enhancement of the reaction product was found to augment the granular nature of nuclear staining, corresponding more closely to patterns observed in cell culture studies. No enhancement was found to be necessary for MIB-1. The labelling indices of all these antibodies were compared with S phase fraction (SPF) obtained by DNA flow cytometry in the same cases. The PC10 labelling indices which included only strongly stained cells correlated well with SPF, but counting all strongly and weakly stained cells showed a poor correlation. With MIB-1, counting strongly stained as well as all stained cells produced labelling indices which correlated well with SPF, the former tending to be lower and the latter higher. None of the other anti-PCNA antibodies showed any advantage in application over PC10. Thus, PC10 and MIB-1, applied with care, can be correlated with S phase fraction in paraffin processed tissue sections of breast carcinomas.

Adenocarcinoma↗

PubMed1994

Immunocytochemical detection of cell proliferation-related antigens in cytologic smears of human malignant neoplasms using PC10, reactive with proliferating cell nuclear antigen, and Ki-67. A comparative study.

Cytospins of the MCF-7 cell line and 93 consecutive smears of human malignant neoplasms were immunochemically evaluated for the expression of proliferating cell nuclear antigen (PCNA) and Ki-67-related antigen. Results expressed as the labeling index (LI) were compared with histologic sections. The PCNA LI and Ki-67 LI were lower in cytologic smears than in histologic sections, though the differences were not statistically significant. A positive linear relationship was found between these markers in both cytologic and histologic samples. The PCNA LI was generally lower than the Ki-67 LI, but in seven malignant neoplasms, PCNA LI was greater than the corresponding values of the KI-67 LI. We conclude that cell proliferation can be reliably evaluated on cytologic preparations; PCNA may behave as a Ki-67-like reagent in some tumors, and PCNA may sometimes overestimate the cell growth fraction assessed by Ki-67 immunoreactivity.

Antigens, Neoplasm↗

PubMedDate not supplied

Proliferating cell nuclear antigen (PCNA) in prostatic invasive adenocarcinoma. Is the proliferation state in the marginal zone of the tumour higher than in the central part?

Expression and location of Proliferating Cell Nuclear Antigen in epithelial nuclei were assessed in invasive adenocarcinoma of the prostate gland. The PCNA-positive nuclei showed homogeneous or granular types of immunostaining or a mixture of both, and a gradation in the intensity of staining. Nuclei with homogeneous pattern appeared darker brown than the lighter granular and mixed patterns. Darker nuclei were quite frequently noted, mainly among the epithelial cells adjacent to the stroma. For the marginal zone of invasive adenocarcinoma, the mean proportion of PCNA-stained nuclei in the small acinar pattern was somewhat similar to that in the large acinar pattern, i.e., 8.66% and 9.06%, respectively. In contrast, the mean values in the cribriform pattern were greater than in the small and large acinar patterns, and decreased from the nuclei in the basal position, or adjacent to the stroma, toward the lumen: 14.40% in the basal position, 11.84% in the intermediate and 9.26% in the lumenal. In the solid/trabecular pattern, the proportions of PCNA-positive nuclei were higher than in all the other patterns: 17.60% in the cell layer adjacent to the stroma and 13.88% in the other layers. The trend of value changes in the central zone of the tumour was similar to that obtained in the marginal zone. However, the proportions were lower and the differences statistically significant. This might indicate that the proliferation state is higher in the marginal zone and that the tumour grows eccentrically rather than centrally.

Adenocarcinoma↗

PubMed1993

[The evaluation of cellular proliferating activity in gastric carcinoma with the proliferating cell nuclear antigen (PCNA) expressive rate: its fundamental examination of the immunohistochemical procedures and its clinical applications].

PCNA is known as a cell cycle-related nuclear antigen. We stained PCNA immunohistochemically, and examined whether or not PCNA expressive rate could be applied clinically for a biological parameter of the histopathological effects in preoperative chemotherapy. PCNA was stained in proliferating cell by measuring nuclear DNA simultaneously. The most suitable fixation time in PCNA expression was 24 hours. On the examination of fixation fluid, ethanol was considered to be more suitable than buffer formaldehyde because PCNA expressive rate in ethanol correlated to BrdU labeling index with statistical significance. We examined PCNA expressive rate in gastric carcinomas. In the group whose histopathological effects of preoperative chemotherapy was recognized to be positive, PCNA expressive rate was significantly lower than in the group of negative effect. We measured thymidylate synthetase inhibition rate (TSIR) in the cases of preoperative oral administration of 5-FU, and the significantly negative correlation was seen between TSIR and PCNA expressive rate in the cases of differentiated adenocarcinoma (p < 0.05). The proliferating activity was recognized to be lower in the cases of higher inhibitional effect for DNA synthesis. PCNA expressive rate was considered to be a more effective and objective biological parameter on the evaluation of malignant potential in gastric carcinoma.

Antigens, Neoplasm↗

PubMed1996

A comparison of proliferation markers and their prognostic value for women with endometrial carcinoma. Ki-67, proliferating cell nuclear antigen, and flow cytometric S-phase fraction.

BACKGROUND: The understanding of proliferation is a central issue in oncology. Several methods exist for the assessment of the growth fraction and cell-cycle time, but comparative studies that give the clinician advice about the most reliable use of new markers are few. The aim of the current study was to perform methodologic, descriptive, comparative, and prognostic studies of Ki-67, proliferating cell nuclear antigen (PCNA), and flow cytometric S-phase fraction (SPF) in endometrial carcinoma. METHODS: The expression of Ki 67 (n = 175) and PCNA (n = 146) were studied immunohistochemically; and the SPF (n = 297) by flow cytometry. The median follow-up time was 78 months. RESULTS: Neither Ki-67 nor PCNA had any correlation to either the stage or the histopathologic subtype of the tumors, but they were covariant with the histopathologic grade (P < 0.05). There was an interrelationship between Ki-67 and PCNA (P < 0.001), and both were associated with the size of the SPF (P < 0.0001 and P < 0.05, respectively). Mean SPF was high in advanced stages and strongly associated with histopathologic subtype (P < 0.0001) and ploidy (P < 0.0001). Tumors with strong Ki-67 expression were more often aneuploid (P < 0.01). In initial analyses, Ki-67 and SPF were predictors of poor survival (P < 0.05 and P < 0.001, respectively), whereas PCNA was not. When SPF was added to a comprehensive multivariate model, Ki-67 provided no further prognostic information, whereas SPF remained a powerful predictor of survival. CONCLUSIONS: Ki-67 and, to a lesser extent, PCNA, give approximate estimates of the growth fraction, whereas SPF only reflects the proportion of cells in S-phase. However, SPF is by far the strongest predictor of survival.

Adult↗

PubMed1997

The effect of incubation of rectal biopsies on measures of proliferation using proliferating cell nuclear antigen in comparison with 5-bromo-2-deoxyuridine.

Rectal epithelial cell kinetics are used as intermediate markers for colorectal cancer and relate to risk. In this study, measures of proliferation using direct immunohistochemistry for proliferating cell nuclear antigen (PCNA) were compared to in vitro labeling by bromodeoxyuridine (BrdUrd) and incubated biopsies that were later stained for PCNA (PCNA-I) in human rectal biopsies. The study group consisted of 20 sets of biopsies from 12 subjects participating in an intervention trial. Fresh nonincubated biopsies were fixed in methacarn and stained immunohistochemically for PCNA (clone 19A2). In parallel biopsies, BrdUrd was incorporated into the DNA of S-phase cells during a 2-h incubation at 37 degrees C under hyperbaric conditions and localized by immunohistochemistry. Additionally, biopsies were incubated under hyperbaric conditions for 2 h at 37 degrees C, fixed in methacarn, and stained for PCNA (PCNA-I). There was a highly significant difference in the labeling index between the three methods (P < 0.01), but there was no significant difference between subjects (P = 0.439). The mean labeling index was 2.3 +/- 0.1% for PCNA, 2.9 +/- 0.1% for PCNA-I, and 4.1 +/- 0.1% for BrdUrd. The proportion of labeled cells in the top two-fifths was significantly higher (P = 0.01) for BrdUrd (5.5 +/- 0.8%) and PCNA-I (6.4 +/- 1.1%) compared to PCNA (3.1 +/- 0.6%), and a significant difference was seen between subjects (P = 0.038). PCNA-I and BrdUrd methods had similar crypt heights with 73.5 +/- 1.8 and 71.2 +/- 1.3 cells/crypt column, respectively, but were significantly shorter (P < 0.001) than PCNA with 83.4 +/- 1.5 cells/crypt column, indicating a loss of cells during organ culture. The simplicity of the PCNA technique, which avoids potential perturbations occurring during organ culture, has considerable appeal as a marker for colorectal cancer risk, but additional studies are needed to correlate PCNA with neoplastic risk.

Adult↗