Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis


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Abstract

Cellular Prion Protein (PrPC) is a cell surface protein highly expressed in the nervous system, and to a lesser extent in other tissues. PrPC binds to the extracellular matrix laminin and vitronectin, to mediate cell adhesion and differentiation. Herein, we investigate how PrPC expression modulates the aggressiveness of transformed cells. Mesenchymal embryonic cells (MEC) from wild-type (Prnp+/+) and PrPC-null (Prnp0/0) mice were immortalized and transformed by co-expression of ras and myc. These cells presented similar growth rates and tumor formationin vivo.When injected in the tail vein,Prnp0/0ras/myccells exhibited increased lung colonization compared withPrnp+/+ras/myccells. Additionally,Prnp0/0ras/myccells form more aggregates with blood components thanPrnp+/+ras/myccells, facilitating the arrest ofPrnp0/0ras/myccells in the lung vasculature. Integrin αvβ3 is more expressed and activated in MEC and in transformedPrnp0/0 cells than in the respectivePrnp+/+cells. The blocking of integrin αvβ3 by RGD peptide reduces lung colonization in transformedPrnp0/0 cells to similar levels of those presented by transformedPrnp+/+cells. Our data indicate that PrPC negatively modulates the expression and activation of integrin αvβ3 resulting in a more aggressive phenotype. These results indicate that PrPC may have main implications in modulating metastasis formation. © 2009 UICC

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