Lea A Moukarzel1, Lorenzo Ferrando2, Higinio Dopeso3, Anthe Stylianou1, Thais Basili3, Fresia Pareja3, Arnaud Da Cruz Paula1, Gabriele Zoppoli4, Nadeem R Abu-Rustum1, Jorge S Reis-Filho3, Kara Long Roche1, William P Tew5, Dennis S Chi1, Yukio Sonoda1, Dmitriy Zamarin5, Carol Aghajanian5, Roisin E O'Cearbhaill6, Oliver Zivanovic1, Britta Weigelt7. 1. Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America; IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. 4. IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine, University of Genoa, Genoa, Italy. 5. Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United States of America. 6. Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United States of America; National University of Ireland, Galway, Ireland. 7. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. Electronic address: weigeltb@mskcc.org.
Abstract
OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues. CONCLUSIONS: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.
OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues. CONCLUSIONS: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.
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