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

Lucia Cottone, Annalisa Capobianco, Chiara Gualteroni, Cristiana Perrotta, Marco E. Bianchi, Patrizia Rovere-Querini, Angelo A. Manfredi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1381-1389
Number of pages9
JournalInternational Journal of Cancer
Volume136
Issue number6
DOIs
Publication statusPublished - Mar 15 2015

Keywords

  • 5-Fluorouracil
  • Autophagy
  • Chemoattraction
  • HMGB1
  • Peritoneal carcinomatosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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