26: Role of the long pentraxin PTX3 in fibrosarcoma development and progression

Abstract

Pentraxins (PTXs) are prototypic components of the humoral arm of innate immunity and constitute a superfamily of multifunctional multimeric proteins phylogenetically conserved from arachnids to mammals. The prototypic long pentraxin PTX3 plays a fundamental role in innate immunity, in regulation of the inflammatory response and in tissue remodeling (1), through different molecular mechanisms, including Complement regulation, P-selectin-dependent leukocyte recruitment and FGF2-regulation. Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion and metastasis. PTX3 is produced by diverse cell types present in the tumor stroma such as leukocytes, endothelial cells and fibroblasts (1, 2). To define the role of PTX3 in tumor development, we investigated the susceptibility to 3-Methylcholanthrene-induced fibrosarcoma or transplanted fibrosarcomas in Ptx3-/- and wild type mice. PTX3-deficiency was associated with increased tumor incidence, fast tumor growth and higher inflammatory response (e.g. leukocyte recruitment, inflammatory cytokines). Furthermore, the analysis of tumors revealed increased complement C3 and reduced Factor H deposition in PTX3-deficient mice, in agreement with the complement-regulatory function of PTX3. Finally, the genetic analysis of “hot” genes Tp53 and K-ras, classically mutated by 3-MCA, showed that PTX3-deficiency was associated with higher mutation frequency, possibly due to polyclonality of the lesions. All together, these results suggest that the regulation of inflammation mediated by PTX3 could play a crucial role in fibrosarcoma development. Mechanisms potentially involved in the mentioned phenotypes, which range from regulation of angiogenesis, complement deposition, leukocyte recruitment and gene instability are currently under investigation. 1. Bottazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 2010;28:157–83. 2. Jaillon S, Peri G, Delneste Y, Fremaux I, Doni A, Moalli F, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007;204:793–804.