Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional
treatment associating surgical resection and subsequent radio-chemotherapy. Among
these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM
stem-like cells appears to be involved in the systematic GBM recurrence. Moreover,
recent studies showed that differentiated tumor cells may have the ability to
dedifferentiate and acquire a stem-like phenotype, a phenomenon also called
plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized
that GBM cells could be subjected to a similar dedifferentiation process after
ionizing radiations (IRs), then supporting the GBM rapid recurrence after
radiotherapy. In the present study we demonstrated that subtoxic IR exposure of
differentiated GBM cells isolated from patient resections potentiated the long-term
reacquisition of stem-associated properties such as the ability to generate primary
and secondary neurospheres, the expression of stemness markers and an increased
tumorigenicity. We also identified during this process an upregulation of the
anti-apoptotic protein survivin and we showed that its specific downregulation led to
the blockade of the IR-induced plasticity. Altogether, these results demonstrated
that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent
pathway. Targeting the mechanisms associated with IR-induced plasticity will likely
contribute to the development of some innovating pharmacological strategies for an
improved radiosensitization of these aggressive brain cancers.
Cytochrome P-450 3A enzymes belong to the most abundant subfamily of the cytochrome P-450 system. They are predominantly found in the liver where they metabolize numerous drugs and endogenous substances such as oestrogens. However, they are also expressed by normal and tumoural extrahepatic tissues. Accordingly, immunolocalization was assessed in malignant breast tumours (nΩ32) and normal counterparts, by using a monoclonal antibody that recognizes all human CYP3A proteins. We investigated a potential relation between expression of CYP3A protein expression, the degree of tumour differentiation assessed by the histological grade and the proliferation index assessed by Ki-67 immunostaining. Immunodetection of CYP3A was observed in 27 of the 32 tumours analyzed (84%). A focal staining was also observed in the adjacent normal breast tissue in 33% of the samples, but expression was always fainter than in tumours. A significant negative association was found between CYP3A and the proliferation index, but there was no relation with receptor status or tumour differentiation. While CYP3A protein expression can be found in normal breast tissues, these data highlight higher and more frequent CYP3A in malignant breast cells. Such expression in malignant breast cells appears inversely related to the proliferation index whereas no relation is found with tumour differentiation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.