PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer

Eduardo Bonavita, Stefania Gentile, Marcello Rubino, Virginia Maina, Roberto Papait, Paolo Kunderfranco, Carolina Greco, Francesca Feruglio, Martina Molgora, Ilaria Laface, Silvia Tartari, Andrea Doni, Fabio Pasqualini, Elisa Barbati, Gianluca Basso, Maria Rosaria Galdiero, Manuela Nebuloni, Massimo Roncalli, Piergiuseppe Colombo, Luigi LaghiJohn D. Lambris, Sébastien Jaillon, Cecilia Garlanda, Alberto Mantovani

Research output: Contribution to journalArticle

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. Video Abstract

Original languageEnglish
Pages (from-to)700-714
Number of pages15
JournalCell
Volume160
Issue number4
DOIs
Publication statusPublished - Feb 12 2015

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bonavita, E., Gentile, S., Rubino, M., Maina, V., Papait, R., Kunderfranco, P., Greco, C., Feruglio, F., Molgora, M., Laface, I., Tartari, S., Doni, A., Pasqualini, F., Barbati, E., Basso, G., Galdiero, M. R., Nebuloni, M., Roncalli, M., Colombo, P., ... Mantovani, A. (2015). PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell, 160(4), 700-714. https://doi.org/10.1016/j.cell.2015.01.004