Hyaluronan (HA), an extracellular high-molecular-mass polysaccharide, is supposed to be involved in the growth and progression of malignant tumours. We studied the cellular expression of HA in 215 operated stage I–IV gastric cancer patients using a specific biotinylated probe. Most (93%) of the tumours showed HA staining in their parenchyma, whereas the stroma inside and around the tumour was stained in every case. When HA expression was compared with the clinical and histological features of the tumours, a strong staining intensity in the tumour parenchyma was found to be associated with deep tumour invasion (pT3 or 4) and with mixed type of Laurén. A high proportion of HA-positive cells of all neoplastic cells was significantly associated with deep tumour invasion, nodal metastasis, positive lymphatic invasion, poor differentiation grade, as well as with inferior prognosis in univariate survival analysis. However, in multivariate analysis, only pT, pN, and vascular and lymphatic invasion emerged as independent predictors of survival in gastric cancer. The results indicate that ectopic HA expression is a frequent feature of gastric adenocarcinoma, and is associated with tumour progression and poor survival rate. © 1999 Cancer Research Campaign

Aims: To evaluate the expression and prognostic relevance of p21 WAF1 in breast cancer and to investigate its association with p53, activator protein 2 (AP-2), and cell proliferation (as assessed by Ki-67 expression). Methods: p21 WAF1 expression was analysed immunohistochemically in a large prospective, consecutive series of 420 patients with breast cancer diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. Inter-relations between p21 WAF1 expression and p53, AP-2, and Ki-67 were evaluated. The expression of p21 WAF1 was also compared with clinicopathological parameters and the patients' survival. Results: In general, nuclear p21 WAF1 expression was low in carcinomas (median, 2.5%; range, 0-70%). Expression was lowest in lobular carcinomas (χ 2 = 7.4; p = 0.025). p21 WAF1 positive tumours were more often p53 positive (χ 2 = 4.2; p = 0.041) but expression of p21 WAF1 did not correlate with AP-2 expression or Ki-67 in the whole patient group. In addition, the combined expression of p21 and p53 was not associated with AP-2 expression. High nuclear p21 WAF1 positivity (n = 160; 38%) was associated with poor differentiation (χ 2 = 8.1; p = 0.017). In the univariate analyses, p21 WAF1 expression had no prognostic value for predicting breast cancer related survival (BCRS) or recurrence free survival (RFS) in the whole patient group or in the subgroups investigated. However, in postmenopausal patients with lymph node metastases, and oestrogen receptor (ER) and/or progesterone receptor (PR) positive tumours, high p21 WAF1 expression predicted response to adjuvant hormonal treatment with antioestrogens. In the univariate analysis, the significant factors for predicting BCRS were Ki-67 expression, stage, lymph node status, histological grade, ER and PR status, and those for RFS were Ki-67 expression, stage, and lymph node status. In the multivariate analysis, the independent predictors of shorter BCRS were high cell proliferation activity measured by Ki-67 expression (p < 0.001), advanced stage (p < 0.001), and poor differentiation (p = 0.048). Shorter RFS was independently predicted by high cell proliferative activity (p < 0.001) and advanced stage (p < 0.001). Conclusions: The regulation of p21 WAF1 seems to occur independently of p53 or AP-2 and analysing p21 WAF1 expression provided no prognostic information for patients with breast cancer.

Tumour suppressor p21 WAF1/CIP1 is the main downstream effector gene mediating p53-induced cell cycle arrest, up-regulated by normal wild-type p53 (El-Deiry et al, 1993). In addition to direct transcriptional induction by the tumour suppressor p53, various other signals can induce p21 expression in the absence of wildtype p53 (Michieli et al, 1994;Zeng and El-Deiry, 1996). Harper et al (1993) showed that the ability of the p21 gene product to arrest the cell cycle is based on its virtue to bind and inhibit active cyclin/CDK complexes needed in DNA replication and cell cycle progression. p21 can also inhibit DNA replication by directly binding to the proliferating cell nuclear antigen (PCNA) molecule, thus inhibiting the ability of DNA polymerase δ to extend new DNA chains but still allowing the DNA repair function to continue (Flores-Rozas et al, 1994;Waga et al, 1994;Podust et al, 1995).In human melanoma cell lines, induction of p21 is independent of wild-type p53 expression (Jiang et al, 1995;Vidal et al, 1995), and elevated expression of p21 is associated with melanoma differentiation, growth arrest and metastatic suppression (Jiang et al, 1995). However, the knowledge of p21 expression in clinical materials of cutaneous malignant melanoma is rather limited. Maelandsmo et al (1996) revealed a significant correlation between elevated p21 expression and increasing tumour thickness in superficially spreading melanoma, but no correlation between p21 and survival was found. Elsewhere, a significant overexpression of p21 has been demonstrated in primary and metastatic melanomas (Trotter et al, 1997).As far as the authors are aware, no previous study has compared the relationships between p21, p53 and PCNA expression in primary stage I cutaneous melanoma. In the present study, we used immunohistochemistry to analyse the above-mentioned relationships in a cohort of 369 patients with long-term follow-up data. In addition, our aim was to analyse whether p21 protein levels are related to clinical data, histological parameters (Clark and Breslow levels) and prognosis. MATERIALS AND METHODS PatientsThe retrospective study consists of a consecutive series of 369 clinical stage I cutaneous malignant melanoma patients with complete clinical and histopathological data available, who were diagnosed and treated in the district of Kuopio University Hospital, Finland, between 1974 and 1989. The clinical staging of all tumours was carried out according to UICC (UICC, 1987). Because of insufficient tumour material, pigment or technical artefacts, there were 267 valid immunostainings for p21, 284 for p53 and 219 for PCNA respectively. Patient records were reviewed and the pertinent clinical and histopathological data of the patients are shown in Table 1. The mean follow-up time of all 369 patients was 6.4 years (range 0.2-18 years). When the analysis was restricted to patients with p21, p53 or PCNA data, the mean follow-up times were 6.3 years (range 0.5-18 years), 6.3 years (range 0.5-18 years) or 7.2 years (range 0.5-18 years) re...

No abstract

No abstract