Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma
Giulia Fianco,
Maria Patrizia Mongiardi,
Andrea Levi,
Teresa De Luca,
Marianna Desideri,
Daniela Trisciuoglio,
Donatella Del Bufalo,
Irene Cinà,
Anna Di Benedetto,
Marcella Mottolese,
Antonietta Gentile,
Diego Centonze,
Fabrizio Ferrè,
Daniela Barilà
Affiliations
Giulia Fianco
Department of Biology, University of Rome Tor Vergata, Rome, Italy; Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
Maria Patrizia Mongiardi
Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
Andrea Levi
Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
Teresa De Luca
Preclinical Models and New Therapeutic Agents Unit, Research, Advanced Diagnostics and Technological Innovation Department, Regina Elena National Cancer Institute, Rome, Italy
Marianna Desideri
Preclinical Models and New Therapeutic Agents Unit, Research, Advanced Diagnostics and Technological Innovation Department, Regina Elena National Cancer Institute, Rome, Italy
Daniela Trisciuoglio
Preclinical Models and New Therapeutic Agents Unit, Research, Advanced Diagnostics and Technological Innovation Department, Regina Elena National Cancer Institute, Rome, Italy
Donatella Del Bufalo
Preclinical Models and New Therapeutic Agents Unit, Research, Advanced Diagnostics and Technological Innovation Department, Regina Elena National Cancer Institute, Rome, Italy
Irene Cinà
Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
Anna Di Benedetto
Pathology Department, Regina Elena National Cancer Institute, Rome, Italy
Marcella Mottolese
Pathology Department, Regina Elena National Cancer Institute, Rome, Italy
Antonietta Gentile
Multiple Sclerosis Clinical and Research Center, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Unit of Neurology and of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli (IS), Italy
Diego Centonze
Multiple Sclerosis Clinical and Research Center, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Unit of Neurology and of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli (IS), Italy
Department of Biology, University of Rome Tor Vergata, Rome, Italy; Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
Caspase-8 is a key player in extrinsic apoptosis and its activity is often downregulated in cancer. However, human Caspase-8 expression is retained in some tumors, including glioblastoma (GBM), suggesting that it may support cancer growth in these contexts. GBM, the most aggressive of the gliomas, is characterized by extensive angiogenesis and by an inflammatory microenvironment that support its development and resistance to therapies. We have recently shown that Caspase-8 sustains neoplastic transformation in vitro in human GBM cell lines. Here, we demonstrate that Caspase-8, through activation of NF-kB, enhances the expression and secretion of VEGF, IL-6, IL-8, IL-1beta and MCP-1, leading to neovascularization and increased resistance to Temozolomide. Importantly, the bioinformatics analysis of microarray gene expression data derived from a set of high-grade human gliomas, shows that high Caspase-8 expression levels correlate with a worse prognosis.
