TY - JOUR
T1 - PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer
AU - Bonavita, Eduardo
AU - Gentile, Stefania
AU - Rubino, Marcello
AU - Maina, Virginia
AU - Papait, Roberto
AU - Kunderfranco, Paolo
AU - Greco, Carolina
AU - Feruglio, Francesca
AU - Molgora, Martina
AU - Laface, Ilaria
AU - Tartari, Silvia
AU - Doni, Andrea
AU - Pasqualini, Fabio
AU - Barbati, Elisa
AU - Basso, Gianluca
AU - Galdiero, Maria Rosaria
AU - Nebuloni, Manuela
AU - Roncalli, Massimo
AU - Colombo, Piergiuseppe
AU - Laghi, Luigi
AU - Lambris, John D.
AU - Jaillon, Sébastien
AU - Garlanda, Cecilia
AU - Mantovani, Alberto
N1 - Funding Information:
We thank N. Polentarutti for technical assistance, S. Meri for generously providing SRC19-20, and B. Bottazzi and P. Bianchi for discussion. The contribution of the European Commission (ERC to A.M., FP7-HEALTH-2011-ADITEC-N°280873), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project FIRB RBLA039LSF), Associazione Italiana Ricerca sul Cancro (AIRC and AIRC 5x1000), and the Italian Ministry of Health is gratefully acknowledged.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/2/12
Y1 - 2015/2/12
N2 - PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3-/- mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation. Video Abstract
AB - PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3-/- mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation. Video Abstract
UR - http://www.scopus.com/inward/record.url?scp=84922689090&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.01.004
DO - 10.1016/j.cell.2015.01.004
M3 - Article
C2 - 25679762
AN - SCOPUS:84922689090
VL - 160
SP - 700
EP - 714
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -