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Wnt ligand-driven tumor growth is inhibited by the soluble Wnt inhibitor Fzd8CRD, but the mechanism through which this effect is mediated is unknown. In the MMTV-Wnt1 mouse model, regression of mammary tumors by Fzd8CRD treatment coincides with an acute and strong induction of insulin-like growth factor (IGF)- binding protein IGFBP5, an antagonist of IGF signaling that mediates involution of mammary gland in females after offspring are weaned. In this study, we show that repression of this IGF inhibitory pathway is crucial for Wntdriven growth of mammary tumors. We found that IGFBP5 regulation was mediated by the β-catenin-dependent Wnt pathway. Wnt, in addition to IGF ligands, facilitated tumor growth by paracrine communication among tumor cells. In addition, Fzd8CRD caused precocious induction of IGFBP5 in normal mammary glands undergoing involution, implying an acceleration of the involution process by inhibition of Wnt signaling. The molecular and phenotypic parallel between tumor regression and mammary gland involution suggests that Wntdriven mammary tumors use the same growth mechanism as proliferating normal mammary glands. [ABSTRACT FROM AUTHOR]

Background: Histological examinations of MMTV-Wnt1 tumors reveal drastic differences in the tumor vasculature whenqcompared to MMTV-Her2 tumors. However, these differences have not been formally described, nor have any angiogenicqfactors been implicated to be involved in the Wnt1 tumors. Methodology/Principal Findings: Here, we show that MMTV-Wnt1 tumors were more vascularized than MMTV-Her2qtumors, and this correlated with significantly higher expression of a CXC chemokine, stromal cell-derived factor-1 (SDF1/qCXCL12) but not with VEGFA. Isolation of various cell types from Wnt1 tumors revealed that SDF1 was produced by bothqtumor myoepithelial cells and stromal cells, whereas Her2 tumors lacked myoepithelial cells and contained significantly lessqstroma. The growth of Wnt1 tumors, but not Her2 tumors, was inhibited by a neutralizing antibody to SDF1, but not byqneutralization of VEGFA. Anti-SDF1 treatment decreased the proportion of infiltrating Gr1+ myeloid cells in the Wnt1 tumors,qwhich correlated with a decrease in the percentage of endothelial cells. The involvement of Gr1+ cells was evident from theqretardation of Wnt1 tumor growth following in vivo depletion of these cells with an anti-Gr1-specific antibody. This degreeqof inhibition on Wnt1 tumor growth was comparable, but not additive, to the effect observed with anti-SDF1, indicative ofqoverlapping mechanisms of inhibition. In contrast, Her2 tumors were not affected by the depletion of Gr1+ cells. Conclusions/Significance: We demonstrated that SDF1 is important for Wnt1, but not for HER2, in inducing murineqmammary tumor and the role of SDF1 in tumorigenesis involves Gr1+ myeloid cells to facilitate growth and/or angiogenesis. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of a-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced a-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, a-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated a-synuclein or DISC1 thatmay be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding. [ABSTRACT FROM AUTHOR]