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

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 PrP C 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 formation in vivo. When injected in the tail vein, Prnp 0/0ras/myc cells exhibited increased lung colonization compared with Prnp+/+ras/myc cells. Additionally, Prnp0/0ras/myc cells form more aggregates with blood components than Prnp+/+ras/myc cells, facilitating the arrest of Prnp0/0ras/myc cells in the lung vasculature. Integrin αvβ3 is more expressed and activated in MEC and in transformed Prnp0/0 cells than in the respective Prnp+/+ cells. The blocking of integrin αvβ3 by RGD peptide reduces lung colonization in transformed Prnp0/0 cells to similar levels of those presented by transformed Prnp+/+ 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.