Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis.
Cellular Prion Protein (PrP(C)) is a cell surface protein highly expressed in the nervous system, and to a lesser extent in other tissues. PrP(C) 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 PrP(C)-null (Prnp(0/0)) 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(0/0)ras/myc cells exhibited increased lung colonization compared with Prnp(+/+)ras/myc cells. Additionally, Prnp(0/0)ras/myc cells form more aggregates with blood components than Prnp(+/+)ras/myc cells, facilitating the arrest of Prnp(0/0)ras/myc cells in the lung vasculature. Integrin alpha(v)beta(3) is more expressed and activated in MEC and in transformed Prnp(0/0) cells than in the respective Prnp(+/+) cells. The blocking of integrin alpha(v)beta(3) by RGD peptide reduces lung colonization in transformed Prnp(0/0) cells to similar levels of those presented by transformed Prnp(+/+) cells. Our data indicate that PrP(C) negatively modulates the expression and activation of integrin alpha(v)beta(3) resulting in a more aggressive phenotype. These results indicate that PrP(C) may have main implications in modulating metastasis formation.
Muras
Angelita G
AG
Cellular and Molecular Biology Group, Ludwig Institute for Cancer Research, São Paulo, SP, Brazil.
Hajj
Glaucia N M
GN
Ribeiro
Karina B
KB
Nomizo
Regina
R
Nonogaki
Sueli
S
Chammas
Roger
R
Martins
Vilma R
VR
D000704:Analysis of Variance; D000818:Animals; D002449:Cell Aggregation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D039564:Integrin alphaV / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D018621:PrPC Proteins; D016271:Proto-Oncogene Proteins c-myc; D018631:ras Proteins