title: PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer.
abstract: 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.
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Eduardo
authors: E
authors: Bonavita
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Stefania
authors: S
authors: Gentile
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Marcello
authors: M
authors: Rubino
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Virginia
authors: V
authors: Maina
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy; Institute of Genetics and Biomedical Research, National Research Council, Rozzano (Milan) 20089, Italy.
authors: Roberto
authors: R
authors: Papait
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Paolo
authors: P
authors: Kunderfranco
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Carolina
authors: C
authors: Greco
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Francesca
authors: F
authors: Feruglio
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Martina
authors: M
authors: Molgora
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Ilaria
authors: I
authors: Laface
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Silvia
authors: S
authors: Tartari
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Andrea
authors: A
authors: Doni
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Fabio
authors: F
authors: Pasqualini
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Elisa
authors: E
authors: Barbati
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Gianluca
authors: G
authors: Basso
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Maria Rosaria
authors: MR
authors: Galdiero
authors: Pathology Unit, L. Sacco Department of Clinical Sciences, University of Milan, Milan 20157, Italy.
authors: Manuela
authors: M
authors: Nebuloni
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Massimo
authors: M
authors: Roncalli
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Piergiuseppe
authors: P
authors: Colombo
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Luigi
authors: L
authors: Laghi
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: John D
authors: JD
authors: Lambris
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors: Sébastien
authors: S
authors: Jaillon
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy. Electronic address: cecilia.garlanda@humanitasresearch.it.
authors: Cecilia
authors: C
authors: Garlanda
authors: Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy; Humanitas University, Rozzano (Milan) 20089, Italy. Electronic address: alberto.mantovani@humanitasresearch.it.
authors: Alberto
authors: A
authors: Mantovani
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism; D019175:DNA Methylation; D016158:Genes, p53; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000276:immunology*; D000683:Serum Amyloid P-Component / Q000235:genetics* / Q000378:metabolism*; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D003165:Complement System Proteins; D000683:Serum Amyloid P-Component; D000099153:Pentraxins