THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS

Abstract The implication of the innate immune system on inflammatory carcinogenesis is a central topic in tumor biology. The humoral pattern recognition molecule PTX3 plays a fundamental role in the modulation of inflammation by regulating Complement cascade and P-selectin dependent neutrophil recruitment. Available information in human and murine 3-MCA induced sarcomas suggests a protective role of PTX3 in cancer-related inflammation. In this study we showed that PTX3-deficient mice were more susceptible to DMBA/TPA chemically-induced epithelial skin cancer than PTX3-competent mice, in term of incidence, multiplicity of papillomas and number of lesions evolving to skin carcinomas, suggesting a more aggressive behavior of PTX3-/- tumors. In the skin, PTX3 was strongly produced during the acute phase of carcinogenesis by infiltrating macrophages, neutrophils, and vessels. Immunohistochemical investigation of papillomas showed low presence of PTX3 in the extracellular matrix. The deficiency of PTX3 was associated with increased cancer-related inflammation in term of neutrophil infiltration, higher production of pro-inflammatory cytokines and chemokines, increased C3 and IgG deposition. In the effort to define the molecular mechanisms underlying this phenotype, we observed that P-selectin deficiency and in vivo neutrophil depletion reverted the tumor susceptibility of Ptx3-/- mice. All together, these results provide evidence that PTX3 is locally produced and plays a protective role in epithelial skin carcinogenesis acting as an extrinsic oncosuppressor. The mechanism of PTX3-mediated protection is explained by modulation of cancer-related inflammation regulating P-selectin dependent neutrophil recruitment and Complement activation.