Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10.

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Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression

Distinct Functionality of Tumor Cell-Derived Gelatinases during Formation of Liver Metastases.

The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell-derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell-derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341-51)

Quantifying Impact of HIV Receptor Surface Density Reveals Differences in Fusion Dynamics of HIV Strains

Human Immunodeficiency Virus (HIV) Type-1 has been studied heavily for decades, yet one area that is still poorly understood is the virus’ ability to cause cell–cell fusion. In HIV, the fusion process is mediated by viral surface glycoproteins that bind to CD4 cell receptors. This virus-mediated cell fusion creates multi-nucleated cells called syncytia that can affect infection dynamics. Syncytia formation is often studied using a cell–cell fusion assay, in which donor cells expressing the viral surface protein fuse with acceptor cells expressing the cell receptor. A mathematical model capable of reproducing the dynamics of the cell–cell fusion assay was recently developed and can be used to quantify changes in syncytia formation. In this study, we use this mathematical model to quantify the changes in syncytia formation in HIV as the surface density of the glycoproteins is varied. We find that we need to modify the model to explicitly include a density-dependent syncytia formation rate that allows us to capture the dynamics of the cell–cell fusion assay as the density of the glycoproteins changes. With this modification, we find that cell–cell fusion of the HXB2 strain, which uses the CXCR4 coreceptor, shows a threshold-like behavior, while cell–cell fusion of the Sf162 strain, which uses the CCR5 co-receptor, shows a more gradual change as surface density decreases

Runaway electron dynamics and transport anisotropy due to resonant magnetic perturbations in ITER

In this paper the effect of resonant magnetic perturbations (RMP) on the net radial transport of runaway electrons (RE) is calculated by simulating the RE drift orbits in magnetostatic perturbed fields. Through the transport, RMP influences the time dynamics andpreferred loss directions of the REs. The distribution of the field mesh exit points of therunaway electrons become more localised compared to the unperturbed case, since the losspattern depends on the geometric properties of the RMP configuration such as periodicityor helicity. On the other hand, the loss patterns do not depend on the particle energiesand starting positions. The particle radial steps are correlated to the local radial magneticperturbation component, which makes the transport chaotic, but deterministic