Reduced body growth and excessive incisor length in insertional mutants mapping to mouse Chromosome 13

Phenotypic and molecular genetic examinations of a transgenic mouse line showing developmental defects caused by a recessive insertional mutation were carried out. The mutant phenotype is characterized by general retardation of postnatal body growth and by the appearance of increased incisor length in the upper and lower jaw. The mutation causing the aberrant phenotype was mapped to Chromosome 13, 40 cM. Examination of the expression of the candidate genes did not show any alterations. This mutant mouse line provides a reproducible model for the identification and examination of gene(s) involved in growth and in the craniofacial development, including that of the jaws and teeth

Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model

Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase (CD) gene to tumors in orthotopic glioma models. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma . Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma

Interferon γ–Induced Human Guanylate Binding Protein 1 Inhibits Mammary Tumor Growth in Mice

Interferon γ (IFN-γ) has recently been implicated in cancer immunosurveillance. Among the most abundant proteins induced by IFN-γ are guanylate binding proteins (GBPs), which belong to the superfamily of large GTPases and are widely expressed in various species. Here, we investigated whether the well-known human GBP-1 (hGBP-1), which has been shown to exert antiangiogenic activities and was described as a prognostic marker in colorectal carcinomas, may contribute to an IFN-γ–mediated tumor defense. To this end, an IFN-independent, inducible hGBP-1 expression system was established in murine mammary carcinoma (TS/A) cells, which were then transplanted into syngeneic immune-competent Balb/c mice. Animals carrying TS/A cells that had been given doxycycline for induction of hGBP-1 expression revealed a significantly reduced tumor growth compared with mock-treated mice. Immunohistochemical analysis of the respective tumors demonstrated a tightly regulated, high-level expression of hGBP-1. No signs of an enhanced immunosurveillance were observed by investigating the number of infiltrating B and T cells. However, hemoglobin levels as well as the number of proliferating tumor cells were shown to be significantly reduced in hGBP-1–expressing tumors. This finding corresponded to reduced amounts of vascular endothelial growth factor A (VEGF-A) released by hGBP-1–expressing TS/A cells in vitro and reduced VEGF-A protein levels in the corresponding mammary tumors in vivo. The results suggest that hGBP-1 may contribute to IFN-γ–mediated antitumorigenic activities by inhibiting paracrine effects of tumor cells on angiogenesis. Consequently, owing to these activities GBPs might be considered as potent members in an innate, IFN-γ–induced antitumoral defense system

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