Proliferating Cell Nuclear Antigen Labeling Research Articles

Cell kinetics of mouse tumour subjected to photodynamic therapy--evaluation by proliferating cell nuclear antigen immunohistochemistry.

Tumour reaction and tumour cell kinetics in mouse NR-S1 carcinoma subjected to photodynamic therapy (PDT) were evaluated by percentage of necrotic area as well as by proliferating cell nuclear antigen (PCNA) immunohistochemistry, and an effective PDT fractionation interval was proposed. PDT was carried out in mouse NR-S1 carcinomas using a photosensitizer (haematoporphyrin oligomers: 20 mg kg body weight) and pulsed Nd:YAG dye laser. The percentages of tumour necrotic area and PCNA labelling indices (LIs) in the tumours were assessed at intervals of 0, 0.5, 5, 2.5, 6, 24, 48, and 72 h after PDT. It was demonstrated that maximum damage and repopulation of the tumour cells emerge at 24 and 48 h, respectively, following PDT, suggesting that subsequent light treatment should be performed within 24 h to enhance the therapeutic effect of PDT.

Plasma-kallikrein clearance during liver regeneration after partial hepatectomy in the rat.

The liver clears circulating plasma-kallikrein through a receptor-mediated endocytosis process: an initial fast phase is followed by a slow exponential phase. To determine whether the clearance rate of plasma-kallikrein is affected during liver regeneration, we perfused isolated rat livers with rat plasma-kallikrein (rPK) at 0, 1, 2, 3 and 7 days after partial hepatectomy or sham operation. Liver regeneration was followed by the expression of the proliferating-cell nuclear antigen (PCNA) labeling index. The serum concentration of alpha2-macroglobulin, an acute phase protein in rats, was measured. At day 1, the fast phase of rPK clearance rate increased in hepatectomized rats when compared with day 0 (4.9+/-0.4 and 3.7+/-0.4 mU/g liver min, p<0.05). However, at day 2, the rPK fast phase clearance rate dropped significantly (2.6+/-0.2, p<0.05), when compared with day 1. No difference was found among the sham groups at different days of hepatectomy. These changes seem to be independent of the acute phase reaction. The regenerative liver weight increased continuously during the observation period. PCNA expression increased significantly after hepatectomy, with maximal PCNA-labeling indices at days 1 and 2, declining thereafter. The rPK fast phase clearance rate changes during liver regeneration, with a zenith occurring when PCNA labeling index is maximal (day 1) and a nadir occurring at the mitotic phase (day 2).

Prognostic value of proliferating cell nuclear antigen immunostaining in pediatric rhabdomyosarcomas.

The levels of proliferating cell nuclear antigen (PCNA) are almost negligible in long-term quiescent cells and increase dramatically during the cell cycle. Recently, the monoclonal antibodies to PCNA have been used to demonstrate the proliferative component of paraffin-embedded tumor tissues. It has been shown to be available as a simple histological marker of proliferative activity and the PCNA labeling index has been correlated with the prognosis of several malignant neoplasms. Formalin fixed, paraffin embedded tissue specimens of 29 primary pediatric rhabdomyosarcomas were immunostained by using an anti-PCNA monoclonal antibody (DAKO PCNA PC10). The relationship between the PCNA index and prognosis, clinicopathological features and survival were assessed retrospectively. The mean PCNA index for the whole series was 54%. There was no correlation between PCNA index and any of the clinicopathological characteristics. However, patients having tumors with a high (> 54%) PCNA index demonstrated significantly lower survival rates than tumors with a low (< 54%) PCNA index (P = 0.01). Moreover, there were significantly more patients with relapse or progressive disease in the high PCNA index group (P = 0.005). The PCNA labeling index can be a useful prognostic factor and a good indicator of recurrence and/or survival in patients with rhabdomyosarcoma.

Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice.

The role of the anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl4). To address the role of endogenous IL-10 production, acute hepatitis was induced by CCl4 in C57Bl/6 IL-10 gene knock out (KO) and wild-type (WT) mice. After CCl4 challenge, serum and liver levels of tumor necrosis factor-alpha (TNF-) and serum levels of transforming growth factor-beta 1 (TGF-beta1) increased and were significantly higher in IL-10 KO mice, whereas IL-6 serum levels were only slightly increased compared with WT mice. At histological examination, the livers disclosed a significantly more prominent neutrophilic infiltration in IL-10 KO mice 12 and 24 hours after CCl4 injection. In contrast, hepatocyte necrosis, evaluated by histological examination and serum alanine aminotransferase levels, was only marginally affected. The proliferative response of hepatocytes, assessed by the proliferating cell nuclear-antigen labeling index, was significantly increased in IL-10 KO mice, compared with WT mice 48 hours after CCl4 injection. Finally, repeated CCl4 injections led to more liver fibrosis in IL-10 KO mice after 7 weeks. In conclusion, endogenous IL-10 marginally affects the hepatocyte necrosis although it controls the acute inflammatory burst induced by CCl4. During liver repair, it limits the proliferative response of hepatocytes and the development of fibrosis.

Expression of apoptotic and proliferation markers in meningiomas.

Fifty-two intracranial, totally excised meningiomas were immunohistochemically analysed for the expression of bcl-2 and p53 proteins, in parallel with the assessment of the proliferating cell nuclear antigen labelling index (PCNA LI) and the mitotic index (MI). bcl-2 was expressed in 26.8 per cent and p53 in 32.6 per cent of the tumours, exhibiting a similar staining pattern, with low levels of immunoreactive cells. The bcl-2-positive/p53-negative subgroup showed a significant association with a benign histological pattern. Expression of bcl-2 appeared to have no influence on the rate of recurrence; p53 expression was the only factor with prognostic significance for recurrence (p = 0.10). There was no interaction between bcl-2 and p53 expression. The PCNA LI was correlated with the MI and the grade of malignancy, proving to be a useful proliferation marker and an additional indicator of the more anaplastic histological patterns in meningiomas. Proliferation indices appeared to have no correlation with the recurrence rate of totally resected tumours. Meningiomas expressing the bcl-2 protein presented a high proportion of proliferating cells in S phase. In contrast, all the tumours which recurred had a minimal S-fraction of proliferating nuclei. These findings may improve our understanding of the interaction between cell proliferation, expression of apoptotic markers, and recurrence in meningiomas.

Inhibition of early-phase exogenous and endogenous liver carcinogenesis in transgenic rats harboring a rat glutathione S-transferase placental form gene.

Hepatocarcinogenesis initiated with N‐nitrosodiethylamine (DEN) and that initiated by feeding of a choline‐deficient, l‐amino acid‐defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S‐transferase placental form (GST‐P) gene (GST‐P‐Tg rats) and non‐transgenic (N‐Tg) rats. Eight‐week‐old GST‐P‐Tg and N‐Tg rats were administered DEN intraperitoneally at 100 mg/kg body weight, subjected to a selection procedure with 2‐acetylaminofluorene and CCl4, and killed at the end of weeks 5 and 12. Other groups were fed the CDAA diet for 12 weeks and killed. Five weeks after the DEN treatment, numbers and sizes of γ‐glutamyltransferase (GGT)‐ or GST‐P‐positive lesions and 8‐hydroxyguanine (8‐OHG) levels in the livers were significantly less in GST‐P‐Tg rats than in N‐Tg rats. The lesion numbers were unchanged between the ends of weeks 5 and 12 in GST‐P‐Tg rats, but decreased in N‐Tg rats. The lesion sizes were increased in GST‐P‐Tg rats, but unchanged in N‐Tg rats. While the proliferating cell nuclear antigen labeling indices (PCNA L.I.) in and surrounding the lesions were decreased, more prominently in GST‐P‐Tg rats than in N‐Tg rats, the 8‐OHG levels were also decreased but similarly in both cases. After 12 weeks on the CDAA diet, the lesion incidences, numbers and sizes, 8‐OHG levels, PCNA L.I. in and surrounding the lesions, and liver injury were significantly less in GST‐P‐Tg rats than in N‐Tg rats. These results indicate that insertion of a rat GST‐P transgene alters the early phase of exogenous and endogenous rat hepatocarcinogenesis, presumably due to enhanced detoxification by GST‐P expressed both transiently during the initiation and chronically in the altered hepatocyte populations.

Proliferative activity of calcifying odontogenic cysts as evaluated by proliferating cell nuclear antigen labeling index.

The calcifying odontogenic cyst (COC) presents with diverse histological features; thus, several subclassifications have been proposed. To evaluate the significance of the various histological features and subtypes of COC from the perspective of proliferative activity, the proliferating cell nuclear antigen (PCNA) labeling index (LI; the percentage of positive nuclei) was assessed immunohistochemically in 25 cases of COC (21 benign and four malignant). All of the benign cases were of the cystic variety and further subclassified into non-proliferative subtype (NPS; four cases); proliferative subtype (PS; eight cases); and COC associated with odontoma (COCaO, nine cases). The PCNA LI of the malignant COC (65.2+/-5.6) was significantly higher than that of the benign COC (11.6+/-9.0; P = 0.002). Non-proliferative subtype (6.8+/-2.8) showed the lowest PCNA LI and PS (17.2+/-11.2) the highest of among the three subtypes of benign cystic COC (P = 0.028). In nine cases of COCaO, six showed epithelial lining of the non-proliferative type as NPS and the other three had lining with proliferative features as PS. The PCNA LI of the latter COCaO group (14.3+/-6.6) was significantly higher than that of the former (6.1+/-4.3; P = 0.05), as seen between PS and NPS. These results demonstrate that PCNA LI is a possible parameter for differentiating malignant COC from benign COC and, whatever the subtypes, the proliferative features in the lining are the main factor influencing the proliferating activity of COC.

Expression of apoptotic and proliferation markers in meningiomas

Fifty-two intracranial, totally excised meningiomas were immunohistochemically analysed for the expression of bcl-2 and p53 proteins, in parallel with the assessment of the proliferating cell nuclear antigen labelling index (PCNA LI) and the mitotic index (MI). bcl-2 was expressed in 26·8 per cent and p53 in 32·6 per cent of the tumours, exhibiting a similar staining pattern, with low levels of immunoreactive cells. The bcl-2-positive/p53-negative subgroup showed a significant association with a benign histological pattern. Expression of bcl-2 appeared to have no influence on the rate of recurrence; p53 expression was the only factor with prognostic significance for recurrence (p =0·10). There was no interaction between bcl-2 and p53 expression. The PCNA LI was correlated with the MI and the grade of malignancy, proving to be a useful proliferation marker and an additional indicator of the more anaplastic histological patterns in meningiomas. Proliferation indices appeared to have no correlation with the recurrence rate of totally resected tumours. Meningiomas expressing the bcl-2 protein presented a high proportion of proliferating cells in S phase. In contrast, all the tumours which recurred had a minimal S-fraction of proliferating nuclei. These findings may improve our understanding of the interaction between cell proliferation, expression of apoptotic markers, and recurrence in meningiomas.Copyright © 1998 John Wiley & Sons, Ltd.

Total blood exchange suppresses the early stage of liver regeneration following partial hepatectomy in rats.

Despite its obscure and short effect, plasma exchange (PE) remains a mainstay in the treatment of liver disease. However, the question still remains as to whether or not PE suppresses the regeneration of the liver because PE deprives patients of hepatotrophic factors. The effect of PE, which could be a total blood exchange (TBE) in a syngeneic setting, on liver regeneration following a 68% partial hepatectomy (PH) was investigated in rats. In Group 1, 20 ml of blood from normal rats was infused while native blood was removed at 6 and 12 h after PH. In Group 2, 20 ml of blood obtained from PH rats at the same time points was infused. The regeneration rate, labeling index of proliferating cell nuclear antigen (PCNA), and plasma hepatocyte growth factor (HGF) level were determined, and standard liver function tests performed at 24, 48, and 72 h. Although all liver function tests improved in Group 1 at 24 and 48 h, the regeneration rate was significantly impaired. Similarly, the PCNA labeling index was significantly lower in Group 1 than that in Group 2. The plasma HGF level was significantly reduced in Group 1 (6 h blood out versus blood in: 1.1+/-0.5 vs. 0.1+/-0.1 ng/ml, p < 0.05). TBE with normal blood following PH suppressed the early stage of liver regeneration, in part, because of the reduction of HGF even though the blood was purified.

Proliferation of goblet cells and vacuolated cells in the rabbit distal colon.

Previous studies of colonic epithelial cell kinetics in mice and rats revealed a pattern similar to small intestine, where basally located stem cells proliferate, differentiating as they migrate towards the surface epithelium. Vacuolated and goblet cells are assumed to co-migrate at the same rate. The present study indicates that rabbit distal colon has more complicated epithelial cell kinetics. The zone of proliferation was detected immunohistochemically using proliferating cell nuclear antigen (PCNA) and confirmed with the use of colchicine to arrest dividing cells in metaphase. Migrating cells were tracked from the zero-hour position (PCNA labeling, mitosis) to positions 24, 48, 72 hrs by monitoring cell migration with the thymidine analog 5-Bromo-2-Deoxyuridine (BrdU). PCNA revealed a major proliferative zone in the upper third of the crypt column and the presence of mitotic figures after colchicine corroborated these results. Differentiated vacuolated cell proliferation was detected at three crypt sites: base, middle, and top of the crypt, while columnar cells arose from a population of dividing cells at the top of the crypt. Turnover of columnar and vacuolated cells occurred within 72 hrs. Goblet cells exhibited maximal proliferation at the crypt base and migrated at a much slower rate than the other cell types. In rabbit distal colon, populations of proliferating cells exist at multiple levels of the crypt column. Vacuolated and goblet cells differ in their labeling indices and migration rates, suggesting that the two cell types arise and migrate independently.

Proliferation of goblet cells and vacuolated cells in the rabbit distal colon

Previous studies of colonic epithelial cell kinetics in mice and rats revealed a pattern similar to small intestine, where basally located stem cells proliferate, differentiating as they migrate towards the surface epithelium. Vacuolated and goblet cells are assumed to co-migrate at the same rate. The present study indicates that rabbit distal colon has more complicated epithelial cell kinetics. The zone of proliferation was detected immunohistochemically using proliferating cell nuclear antigen (PCNA) and confirmed with the use of colchicine to arrest dividing cells in metaphase. Migrating cells were tracked from the zero-hour position (PCNA labeling, mitosis) to positions 24, 48, 72 hrs by monitoring cell migration with the thymidine analog 5-Bromo-2-Deoxyuridine (BrdU). PCNA revealed a major proliferative zone in the upper third of the crypt column and the presence of mitotic figures after colchicine corroborated these results. Differentiated vacuolated cell proliferation was detected at three crypt sites: base, middle, and top of the crypt, while columnar cells arose from a population of dividing cells at the top of the crypt. Turnover of columnar and vacuolated cells occurred within 72 hrs. Goblet cells exhibited maximal proliferation at the crypt base and migrated at a much slower rate than the other cell types. In rabbit distal colon, populations of proliferating cells exist at multiple levels of the crypt column. Vacuolated and goblet cells differ in their labeling indices and migration rates, suggesting that the two cell types arise and migrate independently. Anat. Rec. 252:41–48, 1998. © 1998 Wiley-Liss, Inc.

Feline lymphoma (145 cases): proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats.

Paraffin-embedded, formalin-fixed tissue samples from 145 cats with lymphoma were analyzed for cluster of differentiation 3 (CD3, a surface antigen) immunoreactivity, argyrophilic nucleolar organizer region (AgNOR) frequency, and proliferating cell nuclear antigen labeling index (PCNA-LI). This information along with signalment, anatomic site, and feline leukemia virus (FeLV) antigen status was used to determine the potential of these indicators to predict response to therapy, remission, and survival times, and to characterize cats with lymphoma in the era of general availability of FeLV testing and vaccination. Alimentary lymphoma, primarily occurring in older, FeLV-negative cats, was the most common site of involvement. Although the majority of tumors from FeLV-positive cats were CD3-immunoreactive, only one half of CD3-immunoreactive tumors occurred in FeLV-positive cats. Median remission duration and survival times were 126 days and 143 days, respectively, for all cats. Measures of tumor cell proliferation (AgNOR frequency and PCNA-LI) and CD3-immunoreactivity were not predictive of outcome. When all prognostic factors were accounted for by multivariate analysis, response to therapy, FeLV status, and clinical substage were predictive of outcome. FeLV-negative cats that achieved a complete response following induction therapy were likely to have durable (i.e., > 6-month) responses, particularly when doxorubicin was included in the chemotherapy protocol. However, FeLV-positive cats had significantly shorter remission and survival times with available chemotherapeutic protocols.

Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in invasive ductal carcinoma of the breast in Taiwan

To evaluate the prognostic significance of proliferating cell nuclear antigen (PCNA) in breast cancer, an immunohistochemical assay was performed in 150 patients with invasive ductal carcinomas. The PCNA labeling index (PCNA-LI) was classified into two subgroups at a cut-off point of 45% that gave the best prognostic estimates for PCNA in survival analyses. Seventy-eight tumors had a low PCNA-LI of ≤45% and 72 tumors had a high PCNA-LI of >45%. A high PCNA-LI correlated significantly with p53 overexpression ( P<0.03), positive axillary node ( P<0.04), short disease-free survival ( P<0.001) and overall survival ( P<0.0002), but not with other factors. In multivariate analysis, the PCNA-LI predicted the disease-free ( P<0.008) and overall survival ( P=0.0007) independently. Our study indicates that the PCNA-LI has independent prognostic value.

Evaluation of argyrophilic nucleolar organizer region and proliferating cell nuclear antigen in colorectal cancer.

Information on cellular proliferation is gaining importance for predicting prognosis in several cancers. To clarify the clinicopathological significance of argyrophilic nucleolar organizer region (AgNOR), proliferating cell nuclear antigen (PCNA), and DNA ploidy pattern, we studied their correlations with clinicopathological factors in colorectal cancer. Fifty-two patients with colorectal cancer were examined by AgNOR staining, immunohistochemical study of PCNA expression, and DNA flow cytometry. The AgNOR score and the PCNA labeling rate (PCNA LR) were significantly higher in patients with deep invasion (P = 0.0072, P = 0.0355), liver metastasis (P = 0.0022, P = 0.0001), and Dukes D classification (P = 0.0002, P = 0.0001) than in patients without these factors. In patients with high AgNOR score (>3.83) or with high PCNA LR (>48.8), prognosis was significantly worse (P = 0.0002, P = 0.0123) than in those with low AgNOR score (<3.83) or in those with low PCNA LR (<48.8), respectively. No significant association was observed between AgNOR score and PCNA LR. Combined analysis revealed that the survival curve for patients with high AgNOR score and high PCNA LR was significantly lower (P = 0.0156) than that for patients with high AgNOR score and low PCNA LR. There was no significant correlation between DNA ploidy pattern and clinicopathological findings. PCNA LR and AgNOR score were correlated not only with local progression but also with metastasis. Their determination provided useful prognostic information, and these parameters are probably independent. Their simultaneous determination was useful for accurate evaluation of prognosis. The value of DNA ploidy pattern was uncertain.

Tumor Response to Neoadjuvant Chemotherapy Correlates with the Expression of P-Glycoprotein and PCNA but Not GST-π in the Tumor Cells of Cervical Carcinoma

Objective.To identify the clinicopathological and chemoresistant factors predicting the response to neoadjuvant chemotherapy and the patient prognosis in high-risk cervical carcinomas.Methods.We retrospectively reviewed 47 patients with locally advanced or bulky cervical carcinoma treated with two courses of intraarterial infusion of cisplatin, doxorubicin, mitomycin C, and 5-fluorouracil (5-FU), followed by radical hysterectomy at our hospital between 1988 and 1995. Expressions of the chemoresistance-related proteins, such as P-glycoprotein, glutathioneS-transferase π (GST-π), and proliferating cell nuclear antigen (PCNA) in the tumor cells, were examined by immunohistochemistry using pretreatment biopsy specimens. These results were compared with the chemotherapeutic response, which was evaluated by magnetic resonance imaging (MRI) and histopathology. Outcome of the patients was also studied.Results.Chemotherapeutic effect of either complete (CR) or partial (PR) response on MRI was obtained in 36 of the 47 (86%) patients. Poor response to chemotherapy was significantly correlated with P-glycoprotein expression (P< 0.005) and low PCNA labeling (P< 0.05), but not GST-π expression in the tumor cells. Independent prognostic factors for patient survival were parametrial involvement and lymph node metastasis. Neither the expression of GST-π nor PCNA was correlated with the patient survival.Conclusion.Assessment of the expression of P-glycoprotein and PCNA is potentially useful for the prediction of tumor response to neoadjuvant chemotherapy for cervical carcinomas.

Regenerative response in acute renal failure due to vitamin E deficiency and glutathione depletion in rats

In this study, we investigated some factors contributing to renal regeneration after acute renal failure (ARF) induced by vitamin E (VE) deficiency and glutathione (GSH) depletion. Acute renal failure was induced by feeding rats a vitamin E-deficient diet for 6 weeks and then injecting buthionine sulfoximine (BSO), a glutathione-depleting agent. The level of hepatocyte growth factor (HGF), a renotropic factor for regeneration in the kidney, showed a transient increase at 5 hr after the BSO treatment. Subsequently, renal ornithine decarboxylase (ODC) activity, a marker of G 1 phase, and labeling index (LI) of proliferating cell nuclear antigen (PCNA), a marker of DNA synthesis (S phase), reached peaks at 10 and 53 hr after the injection, respectively. Thus, it appears that the increase in ornithine decarboxylase activity and subsequent elevation in proliferating cell nuclear antigen labeling index following the increase in the hepatocyte growth factor level in the kidneys are closely related to the renal regenerative response after acute renal failure.

Computerized nuclear morphometry of hepatocellular carcinoma and its relation to proliferative activity.

Nuclear profiles have been reported as useful prognostic predictor in various cancers. Data from computerized morphometries are objective and can be quickly derived using conventional microscopic analysis. However, it remains to be shown what types of pathological and biological factors influence the nuclear features. The aim of this study was to evaluate the correlation between the morphological nuclear features and clinicopathological parameters in patients with hepatocellular carcinoma (HCC). Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 76 patients with hepatocellular carcinoma who underwent hepatectomy at our hospital. In each case, 300 cancer nuclei were analyzed randomly on routine hematoxylin&eosin-stained slides through the use of a computer-assisted image analysis system that allowed us to trace the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patient survival, clinicopathologic status, and the proliferative activity of cancer cells. The mean nuclear area of poorly differentiated carcinoma was significantly larger than that of moderately and well differentiated carcinoma (P = 0.0003). Significant correlation was detected between the nuclear area of cancer cells and proliferative activity associated with proliferating cell nuclear antigen labeling index (PCNA LI) of cancer cells (r = 0.372, P = 0.0008). Moreover, blood vessel invasion of cancer cells or intrahepatic metastasis were more frequently detected in patients with large nuclear areas. Even though the nuclear area was not an independent prognostic factor in the multivariate analysis, the 5-year survival rate of the 35 patients who had tumors with large nuclear areas (>50 microm2, 25.9%) was significantly lower than that of the 36 patients who had tumors with small nuclear areas (< or =50 microm2, 63.3%, P = 0.001). The nuclear area of HCC correlates with cell differentiation and cell proliferative activity. Moreover, HCC with a large nuclear area has high potential for blood vessel invasion and intrahepatic metastasis. Thus, nuclear morphometry can be used as an useful morphological predictor for malignant potential in patients with HCC.

A comparative study of nucleolar organizer region, proliferating cell nuclear antigen and epidermal growth factor receptor staining in colon tumours

Several studies have reported that proliferating cell nuclear antigen (PCNA), nucleolar organizer regions (NOR) and epidermal growth factor receptor (EGF-R) are cellular proliferation parameters in malignant tumours. However, the correlation of EGF-R with PCNA and NOR has not been reported in colon tumours. To clarify this, we investigated the correlation of the expression of EGF-R with PCNA and NOR in colonic epithelial tumours. Using immunohistochemical staining and one-step silver staining techniques, the expressions of EGF-R-, PCNA- and NOR-associated protein were studied in paraffin sections from five normal mucosae, 10 adenomas with mild atypia, 16 adenomas with moderate atypia, 32 adenomas with severe atypia including carcinoma in situ and 47 with invasive colon carcinomas. Significant differences were found among the respective degrees of atypia in Ag-NOR counts, PCNA labelling index (LI), and the expression of EGF-R. However, there were no significant differences among the Ag-NOR counts of the severe atypia and invasive carcinoma. There was a significant positive correlation between Ag-NOR counts and PCNA LI (P < 0.001). The Ag-NOR counts and PCNA LI in EGF-R-positive cases were higher than in EGF-R-negative cases (P < 0.001). These results indicate that each of the parameters increased significantly with the increase in atypia and the progression of cancer. Epidermal growth factor receptor provokes an exacerbation of protein synthesis and the cell cycle in colonic epithelial tumours.

Numeric aberration of chromosome 17 is strongly correlated with p53 overexpression, tumor proliferation and histopathology in human bladder cancer.

This study investigated the relationships between the numeric aberrations of chromosome 17 and p53 expression, the proliferating cell nuclear antigen labeling index (PCNA-LI) and histopathology, to determine their prognostic significance in bladder cancer. Using in situ hybridization (ISH) with a biotin-labeled chromosome-specific DNA probe, the copy number of pericentromeric sequences in chromosome 17 were detected within interphase nuclei in formalin-fixed paraffin-embedded sections from 59 nonmetastasized transitional cell carcinomas (TCCs) of the urinary bladder. Expression of p53 and PCNA-LI were determined in serial sections by an immunohistochemical method. The percentage of hyperdiploid cells for chromosome 17 correlated with p53 overexpression (P< 0.002), PCNA-LI (P< 0.002), increasing tumor grade (P< 0.002) and advanced pathologic stage (P< 0.002). The average percentage of hyperdiploid cells was lower in tumors with negative p53 expression than in tumors with p53 overexpression (P< 0.002). Also, more polysomic TCCs were found in muscle-invasive than in superficial cases (P< 0.01 ), and there was a difference in both p53 overexpression or PCNA-LI between disomic and polysomic TCCs (P< 0.01). Patients with chromosome 17 disomic tumors showed less frequent tumor progression than patients with polysomic tumors (P< 0.05). However, chromosome 17 polysomy was an independent prognostic indicator only for patient survival (P< 0.05). The occurrence and extent of numeric aberrations of chromosome 17 may be associated with the evolution of aggressive growth in TCC and may be a useful indicator for survival.

Combined Expression of HLA-DR Antigen and Proliferating Cell Nuclear Antigen Correlate with Colorectal Cancer Prognosis

HLA-DR antigen expression and the proliferating cell nuclear antigen labeling index (PCNA-LI) were examined immmunohistochemically in 59 surgically resected advanced colorectal cancers to clarify the clinicopathologic significance of the HLA-DR antigen. HLA-DR antigen expression was detected in 33 (56%) of the 59 lesions, which showed less frequent liver metastasis than lesions without HLA-DR antigen expression (40 vs. 68%; p < 0.05). Five-year survival rates of patients with and without HLA-DR antigen expression were 50 and 19%, respectively. Lesions combining HLA-DR antigen expression and a relatively low PCNA-LI had the best prognosis. These results indicate that HLA-DR antigen expression, particularly combined with a low PCNA-LI, is an important outcome predictor in colorectal cancer.