Hypotonic stress enhances colon cancer cell death induced by platinum derivatives and immunologically improves anti-tumor efficacy of intraperitoneal chemotherapy.
Fiche publication
Date publication
juillet 2019
Journal
International journal of cancer
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François, Dr REBE Cédric, Dr CHALMIN Fanny, Dr DERANGERE Valentin
Tous les auteurs :
Demontoux L, Derangère V, Pilot T, Thinselin C, Chevriaux A, Chalmin F, Bouyer F, Ghiringhelli F, Rébé C
Lien Pubmed
Résumé
Colorectal cancer is a highly metastatic disease that could invade various distal organs and also the peritoneal cavity leading to peritoneal carcinomatosis. This is a terminal condition with poor prognosis and only palliative treatments such as cytoreductive surgery and intraperitoneal chemotherapy, are proposed to some patients. However clinicians use different parameters of treatments without any consensus. Here we decided to evaluate the effect of osmolarity in the efficacy of this procedure to kill colon cancer cells. We first show that a short exposure of platinum derivatives in hypotonic conditions is more efficient to decrease cell viability of human and murine colon cancer cells in vitro as compared to isotonic conditions. This is related to a more important incorporation of platinum and the capacity of hypotonic stress to induce the copper transporter CTR1 oligomerization. Oxaliplatin in hypotonic conditions induces caspase-dependent cell death of colon cancer cells. Moreover hypotonic conditions also modulate the capacity of oxaliplatin and cisplatin (but not carboplatin) to induce immunogenic cell death (ICD). In vivo, oxaliplatin in hypotonic conditions increases CD8 T cell tumor infiltration and activation. Finally in a murine peritoneal carcinomatosis model, oxaliplatin in hypotonic conditions is the only tested protocol which is able to slow down the appearance of tumor nodules and increase mice survival, while showing no effect in CD8 T cells depleted mice or in immunodeficient mice. Altogether, our study provides new information both in vitro and in a preclinical model of peritoneal carcinomatosis, which highlights the importance of hypoosmolarity in intraperitoneal chemotherapy. This article is protected by copyright. All rights reserved.
Mots clés
cell death, hypotonic stress, immunogenic cell death, peritoneal carcinomatosis, platinum derivatives
Référence
Int. J. Cancer. 2019 Jul 25;: