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Cell. 2015 Feb 12;160(4):700-714. doi: 10.1016/j.cell.2015.01.004.

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

Author information

1
Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
2
Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy; Institute of Genetics and Biomedical Research, National Research Council, Rozzano (Milan) 20089, Italy.
3
Pathology Unit, L. Sacco Department of Clinical Sciences, University of Milan, Milan 20157, Italy.
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy. Electronic address: cecilia.garlanda@humanitasresearch.it.
6
Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy; Humanitas University, Rozzano (Milan) 20089, Italy. Electronic address: alberto.mantovani@humanitasresearch.it.

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.

PMID:
25679762
DOI:
10.1016/j.cell.2015.01.004
[Indexed for MEDLINE]
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