5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells.

Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies.