Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and histological aggressiveness of the breast lesion

The aim of this investigation was to study the expression of caspases 3, 6 and 8 and their association to apoptosis in preneoplastic and neoplastic lesions of the breast. The material consisted of nine benign breast epithelial hyperplasias, 15 atypical hyperplasias, 74 in situ and 82 invasive carcinomas. The extent of apoptosis was assessed by the TUNEL method and caspase 3, 6 and 8 expression by immunohistochemistry with specific antibodies. Increased caspase 3 immunopositivity, as compared to staining of normal breast ductal epithelium, was seen in 22% of benign epithelial hyperplasias, 25% of atypical hyperplasias, 58% of in situ carcinomas and 90% of invasive carcinomas. The corresponding percentages for caspase 6 and 8 were 11%, 25%, 60%, 87% and 22%, 57%, 84%, 83% respectively. In high-grade in situ lesions there were significantly more cases with strong caspase 3, 6 and 8 immunoreactivity than in low- and intermediate-grade lesions (P = 0.0045, P = 0.049 and P = 0.0001 respectively). In invasive carcinomas, however, no association between a high tumour grade and caspase 3, 6 or 8 expression was found (P = 0.27, P = 0.26 and P = 0.69 respectively). The mean apoptotic index was 0.14 ± 0.14% in benign epithelial hyperplasias, 0.17 ± 0.12% in atypical hyperplasias, 0.61 ± 0.88% in in situ carcinomas and 0.94 ± 1.21% in invasive carcinomas. In all cases strong caspase 3, 6 and 8 positivity was significantly associated with the extent of apoptosis (P < 0.001, P = 0.015 and P = 0.050 respectively). The results show that synthesis of caspases 3, 6 and 8 is up-regulated in neoplastic breast epithelial cells in parallel to the increase in the apoptotic index and progression of the breast lesions. © 1999 Cancer Research Campaig

Differential involvement of caspases in apoptosis of myeloid leukemic cells induced by chemotherapy versus growth factor withdrawal.

AbstractTo assess the potential involvement of the caspase family in the IL-3-dependent murine myeloid leukemic cell line 32D, we studied the effect of bcl-2, crmA and three synthetic caspase inhibitors on apoptosis induced by chemotherapy or IL-3 withdrawal. Apoptosis induced by IL-3 deprivation or by ActD appears to be mediated by a crmA-insensitive pathway. Cell death by IL-3 withdrawal is inhibited by the caspase-inhibitor ZVAD-fmk, but not DEVD-fmk or YVAD-cmk. In contrast, DEVD-fmk as well as ZVAD-fmk protect 32D cells from ActD-induced apoptosis. These results indicate that different caspases are involved in apoptosis induced by growth factor withdrawal and by chemotherapy

Expression of co-stimulatory and adhesion molecules and chemokine or apoptosis receptors on acute myeloid leukaemia:high CD40 and CD11a expression correlates with poor prognosis

The expression of adhesion and co-stimulatory molecules. and chemokine and death receptors such as tumour necrosis factor (TNF) and FAS on acute myeloid leukaemia (AML) may influence the biology of the disease and response to chemotherapy and immunotherapy. In this study, we analysed the expression of these molecules in 99 AML patients using monoclonal antibodies and flow cytometry, and correlated the expression with French-American-British (FAB) classification and survival. The following molecules were studied: the co-stimulatory molecules CD80. CD86 and CD40: the adhesion molecules CD11a-c, CD31. CD43. CD50, CD54, CD102. CD58 and CD62L: the chemokine receptor CXCR4: and the death receptors TNFR1 and TNFR2 and FAS. The expression of all molecules was significantly higher in the M4/M5 FAB subgroups except for CD80, CD43. CD54 and CD62L. The AML M3 subgroup had a significant lower expression of CD11a (P=0.02) and CD11c (P=0.03). Five-year survival was significantly shorter in cases of high CD40 expression [>20% positive cells. relative risk (RR) 2.56, P=0.02] or high CD11a expression (>80% positive cells, RR 2.6. P=0.03). This effect was most prominently present in the AML M4/M5 FAB subgroups. We conclude that the expression levels of adhesion and co-stimulatory molecules, CXCR4 and apoptosis-receptors are predominantly FAB subtype-related with high CD40 and CD11a expression as poor prognostic factors