Background
Anti-angiogenic compounds are currently used in the treatment of solid tumors. However their efficacy is far from that expected from preclinical results. This observation likely reflects multiple mechanisms of resistance and genetic traits characterizing responder and non responder subjects. The current evidences suggest that there are at least three distinct mechanisms that manifest evasive resistance: first, upregulation of alternative pro-angiogenic circuits; second, trigger of hypoxia-dependent mechanisms (including the recruitment of vascular progenitors and pro-angiogenic myeloid cells from bone marrow and the increased tumor cell invasiveness to escape oxygen deprivation); and third increased pericyte coverage of tumor vasculature, serving to support its integrity and reduce the requirement of pro-survival signals.
Achievements
(i) Firstly we reported that tyrosine kinase receptors VEGFR-2 and Tie-1, which are respectively triggered by VEGF-A and angiopoietins, form complexes with different types of integrins, which modeulate their responses. (ii) In embryo life the regulation of VEGFR-2 by other membrane proteins including integrins and neuropilin-1 is implicated in the differentiation fate of neuron-endothelial precursors towards neural and vascular cells. (iii) The complexity of these interactions has been modeled through system equations that starting from “wet” biological data simulate and predict the behavior of VEGFR-2 –mediated signaling pathway in endothelial cells. (iv) Finally we are improving biomarker amgiogenic detection in plasma and in tissues by taking advantages of properties of nanomaterials. We established an electromechanical devise based on silica microcantilever to assay angiopoietin.-1 in plasma and silica nanoparticles functionalized with specific antibodies to improve the fluorescence signals by confocal microscopy.
Goals
The final goal of this unit is to elucidate the ping-pong between cancer and stromal cells in modifying tumor angiogenesis.This aim will be pursued as follows: (i) by using isogenic cell lines carrying specific oncogene mutations we’ll study their interaction with stromal and endothelial cells in tridimensional cell systems and the response of endothelial cells to anti-angiogenetic compounds; (ii) by analyzing tumor growth in mice with altered fibroblast or endothelial behavior obtained by loss-of-function experiments with specific shRNA cloned in inducible lentivirus vectors; (iii) through a systems biology approach, by studying the behavior of signaling network down-stream VEGF receptors to identify nodes as new therapeutic targets node; (iv) by the analysis of gene expression profile from stomal cells isolated from neoplastic tissues from non responder patients to anti-angiogenic therapy.
Internal collaboration
Labs of Molecular Genetics and Oncogenomics: isogenic cell line, gene expression analysis; Lab of Tumor microenvironment: phage display technology; Lab of Transgenic Mouse Models: animal models; Lab of Systems Biology: theoretical approaches.
