Systemic chemotherapy induces microsatellite instability in the peripheral blood mononuclear cells of breast cancer patients

INTRODUCTION: Systemic chemotherapy is an important part of treatment for breast cancer. We conducted the present study to evaluate whether systemic chemotherapy could produce microsatellite instability (MSI) in the peripheral blood mononuclear cell fraction of breast cancer patients. METHODS: We studied 119 sequential blood samples from 30 previously untreated breast cancer patients before, during and after chemotherapy. For comparison, we also evaluated 20 women who had no relevant medical history (control group). RESULTS: In 27 out of 30 patients we observed MSI in at least one sample, and six patients had loss of heterozygosity. We found a significant correlation between the number of MSI events per sample and chemotherapy with alkylating agents (P < 0.0001). We also observed an inverse correlation between the percentage of cells positive for hMSH2 and the number of MSI events per sample (P = 0.00019) and use of alkylating agents (P = 0.019). CONCLUSION: We conclude that systemic chemotherapy may induce MSI and loss of heterozygosity in peripheral blood mononuclear cells from breast cancer patients receiving alkylating agents, possibly mediated by a chemotherapy-induced decrease in the expression of hMSH2. These effects may be related to the generation of secondary leukaemia in some patients, and may also intensify the genetic instability of tumours and increase resistance to treatment

Synthesis, chaperoning, and metabolism of proteins are regulated by NT-3/TrkC signaling in the medulloblastoma cell line DAOY.

The human medulloblastoma cell line DAOY was transfected with Tropomyosin receptor kinase (TrkC), a marker for good prognostic outcome. Following TrkC-activation by its ligand neurotrophin-3, protein extracts from DAOY cells were run on 2DE with subsequent MALDI-TOF-TOF analysis and quantification in order to detect downstream effectors. Protein levels of translational, splicing, processing, chaperone, protein handling, and metabolism machineries were shown to depend on neurotrophin-3-induced TrkC activation probably representing pharmacological targets

Age-dependent accumulation of recombinant cells in the mouse pancreas revealed by in situ fluorescence imaging

Mitotic homologous recombination (HR) is critical for the repair of double-strand breaks, and conditions that stimulate HR are associated with an increased risk of deleterious sequence rearrangements that can promote cancer. Because of the difficulty of assessing HR in mammals, little is known about HR activity in mammalian tissues or about the effects of cancer risk factors on HR in vivo. To study HR in vivo, we have used fluorescent yellow direct repeat mice, in which an HR event at a transgene yields a fluorescent phenotype. Results show that HR is an active pathway in the pancreas throughout life, that HR is induced in vivo by exposure to a cancer chemotherapeutic agent, and that recombinant cells accumulate with age in pancreatic tissue. Furthermore, we developed an in situ imaging approach that reveals an increase in both the frequency and the sizes of isolated recombinant cell clusters with age, indicating that both de novo recombination events and clonal expansion contribute to the accumulation of recombinant cells with age. This work demonstrates that aging and exposure to a cancer chemotherapeutic agent increase the frequency of recombinant cells in the pancreas, and it also provides a rapid method for revealing additional factors that modulate HR and clonal expansion in vivo

The Glial Differentiation Factor Nuclear Factor One B (Nfib) Induces Differentiation and Inhibits Growth of Glioblastoma.

International audienceThe molecule CD90 is a N-glycosylated, glycophosphatidylinositol anchored cell surface protein, originally described on thymocytes. CD90 has been considered as a surrogate marker for a variety of stem cells and has recently been reported on glioblastoma stem cells. CD90 is also expressed on T lymphocytes, endothelial cells, fibroblasts and neurons. The function of CD90 is not fully elucidated. CD90 has been involved in cell-cell and cell-matrix interactions, in neurite outgrowth, T cell activation and apoptosis. In this study, we confirmed the expression of CD90 on human glioblastoma stem-like cells from serum-free neurosphere cultures. We also observed RNA and protein CD90 expression on primary cell lines from FSC-containing culture (adherent cell lines) and on freshly prepared glioblastoma specimen. In order to study the function of CD90 on glioblastoma cells, we used a silencing strategy to decrease the expression of CD90 on the immortalized U251 cell line. We then compared the viability, the tumor growth and the migration property of the wild-type CD90+ U251 cells and CD90 down-regulated U251 clones. The decrease of CD90 expression did not affect the viability and the tumor growth of U251 cells. In contrast, down-regulation of CD90 mediated the decreased ability of tumor cell migration using both scratch wound healing and boyden chamber migration assays. Experiments are currently on going to test the effect of CD90 expression on tumorigenicity in mice models. In total, this study might lead to better understand the role of CD90 on the pathology in particular in term of tumor migration/invasion of human glioblastoma