Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis.

Tanja Grimmig,Jennifer Kreckel,Joerg Pelz,Malte Vetterlein,Eva-Maria Moll,Sudipta Tripathi,Simone Callies,Romana Moench,Ana Maria Waaga-Gasser,Christoph-T Germer,Carmen M Ribas,Buelent Polat,Kerstin Kloos,Martin Gasser,Roberta Rehder,Rebecca Thumm,Anil Chandraker

doi:10.1177/1179064417730559

Abstract

In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5-fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy.

Highlights

Peritoneal carcinomatosis (PC) is in strong context with morbidity and mortality in the management of several abdominal cancers, including colorectal, gastric, and ovarian cancers.[1]
HSP27, HSP70, and HSP70/90 inhibition using 17-AAG (HSP90) Western blot analysis was performed in 3 human colon cancer cell lines (HT-29, SW480, and SW620) 24, 48, and 72 hours after exposure to hyperthermia with or without additional chemotherapy using 5-FU, mitomycin C (MMC), and OXA
24 hours after incubation with or without MMC no relevant changes in HSP27 expression were detected in HT-29 cells, upregulated expression as in SW480 for 5-FU tumor cells was demonstrated after 48 and 72 hours: hyperthermia alone resulted in intense HSP27 expression compared with normothermic controls and additional exposure to MMC caused further increase in expression (Figure 2A)

Summary

Introduction

Peritoneal carcinomatosis (PC) is in strong context with morbidity and mortality in the management of several abdominal cancers, including colorectal, gastric, and ovarian cancers.[1]. *T.G. and E-M.M. contributed to this work. Few decades and resulted in a combined strategy of cytoreductive surgery (CRS) of all macroscopic intraperitoneal tumors with hyperthermic intraperitoneal chemotherapy (HIPEC). Today, this combined treatment (CRS and HIPEC) is increasingly accepted as a therapeutic option in some primary and secondary peritoneal malignancies.[4] Commonly used chemotherapeutic agents for HIPEC are mitomycin C (MMC) as well as oxaliplatin (OXA), the latter one with or without additional intravenous 5-fluorouracil (5-FU) treatment. In patients with PC from colorectal origin under such therapy, the 5-year overall survival rate was reported to range between 25% and 47%.5–7 As a consequence, an increasing number of tumor centers have been applying this combined therapeutic regimen.[8,9,10,11,12,13]

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Results

Conclusion