Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

The factors that determine whether disseminated transformed cells in vivo yield neoplastic lesions haveonly been partially identified. We established an ad hoc model of peritoneal carcinomatosis by injectingcolon carcinoma cells in mice. Tumor cells recruit inflammatory leukocytes, mostly macrophages, andgenerate neoplastic peritoneal lesions. Phagocyte depletion via clodronate treatment reduces neoplasticgrowth. Colon carcinoma cells release a prototypic damage-associated molecular pattern (DAMP)/alarmin,High Mobility Group Box1 (HMGB1), which attracts leukocytes. Exogenous HMGB1 accelerates leukocyterecruitment, macrophage infiltration, tumor growth and vascularization. Lentiviral-based HMGB1knockdown or pharmacological interference with its extracellular impair macrophage recruitment andtumor growth. Our findings provide a preclinical proof of principle that strategies based on preventingHMGB1-driven recruitment of leukocytes could be used for treating peritoneal carcinomatosis.