The presence of FGF2 signaling determines whether beta-catenin exerts effects on proliferation or neuronal differentiation of neural stem cells

Neural stem cells proliferate and maintain multipotency when cultured in the presence of FGF2, but subsequent lineage commitment by the cells is nevertheless influenced by the exposure to FGF2. Here we show that FGF2 effects on neural stem cells are mediated, in part, by beta-catenin. Conversely, the effects of beta-catenin in neural stem cells depend in part upon whether there is concurrent fibroblast growth factor (FGF) signaling. FGF2 increases beta-catenin signaling through several different mechanisms including increased expression of beta-catenin mRNA, increased nuclear translocation of beta-catenin, increased phosphorylation of GSK-3beta, and tyrosine phosphorylation of beta-catenin. Overexpression of beta-catenin in the presence of FGF2 helps to maintain neural progenitor cells in a proliferative state. However, overexpression of beta-catenin in the absence of FGF2 enhances neuronal differentiation. Further, chromatin immunoprecipitation (ChIP) assays demonstrate that both beta-catenin and Lef1 bind directly to the neurogenin promoter, and luciferase reporter assays demonstrate that beta-catenin is directly involved in the regulation of neurogenin 1 and possibly other proneural genes when neural stem cells are cultured in the presence of FGF2. We suggest that the balance between the mitogenic effects and the proneural effects of beta-catenin is determined by the presence of FGF signaling.     

Antitumor efficacy and intratumoral distribution of SN-38 from polymeric depots in brain tumor model

We investigate antitumor efficacy and 2D and 3D intratumoral distribution of 7-ethyl-10-hydroxycamptothecin (SN-38) from polymeric depots inside U-87MG xenograft tumor model in nude mice. Results showed that polymeric depots could be used to administer and controlled release of a large amount of SN-38 directly to the brain tumor model. SN-38 released from depots suppressed tumor growth, where the extent of suppression greatly depended on doses and the number of depot injections. Tumor suppression of SN-38 from depots was three-fold higher in animals which received double injections of depots at high dose (9.7 mg of SN-38) compared to single injection (2.2 mg). H&E staining of tumor sections showed that the area of tumor cell death/survival of the former group was two-fold higher than those of the latter group. Fluorescence imaging based on self-fluorescent property of SN-38 was used to evaluate the intratumoral distribution of this drug compared to histological results. The linear correlation between fluorescence intensity and the amount of SN-38 allowed quantitative determination of SN-38 in tumor tissues. Results clearly showed direct correlation between the amount of SN-38 in tumor sections and cancer cell death. Moreover, 3D reconstruction representing the distribution of SN-38 in tumors was obtained. Results from this study suggest the rationale for intratumoral drug administration and release of drugs inside tumor, which is necessary to design drug delivery systems with efficient antitumor activity.