Showing papers by "Davide Ruggero published in 2005"

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

The Akt of translational control

Abstract: The oncogene AKT (also called protein kinase B (PKB)) signals to the translational machinery, and activation of protein synthesis by Akt is associated with cancer formation. Akt directly stimulates the activity of translation initiation factors and upregulates ribosome biogenesis. Activation of protein synthesis by Akt is phylogenetically conserved from Drosophila to humans, and is important for regulating cell growth, proliferation and cell survival. Consequently, translation defects due to aberrant Akt activation may be a crucial mechanism leading to tumorigenesis. However, few in vivo studies have established a causative role for aberrant protein synthesis control in cancer. A major challenge in the future will be to identify the specific mRNAs regulated at the level of translation control directly relevant for cellular transformation. In this review, we highlight and discuss the emerging molecular and genetic evidence that support a model by which deregulation of specific or global protein synthesis contributes to cancer.