Using an in-vitro Colorectal Cancer Construct Platform to Investigate the Potential Genetic Modifications That Occur Due to Hyperthermic Intraperitoneal Chemotherapy.
Loading...
Date
2023-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
Colorectal cancers (CRC) are the fourth most diagnosed cancer and the third leading cause of cancer-related deaths in the United States according to the [1]. One leading therapy for patients with severe, metastatic, and advanced-staged CRC or other abdominal cancers is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). While certain patient characteristics are associated with better outcomes, the cytological differences between candidates who are and are not selected for HIPEC are not well understood. In this study, we describe using bioengineered 3D tumor constructs to mechanistically investigate how HIPEC treatment works. Our goal is to identify key genes and pathways induced by the additional heat applied during HIPEC. We modeled HIPEC statically using Caco-2, SW480, and HCT-116 colorectal cancer cell lines in 3D bioengineered tumor constructs. After two days of organoid culture, they were subjected to oxaliplatin (OXA) (200 mg/m2) and mitomycin-C (MMC) (40 mg/3L) at 37ºC and 42ºC for 120 minutes. The organoids underwent ATP and LIVE cell assays after the drug treatment and on day five. When comparing the 37ºC and 42ºC conditions, our initial studies reveal that the increased temperature used during HIPEC does improve MMC's effectiveness for increasing cell death in HCT116 and MMC's and OXA's effectiveness for increasing cell death SW480 cell lines. Currently, bulk RNA sequencing is being performed to investigate transcriptomic changes due to temperature. After two days of culturing, the organoids are subjected to similar heat temperatures without drugs and RNA was extracted. An RNA sequencing cluster analysis will be performed to identify the genomic changes that occur during a HIPEC treatment. It may be able to redefine the patient selection process, establish an effective in-vitro colorectal microenvironment, and expand the opportunity for precision medicine within the clinical setting.
Description
Keywords
Hyperthermic Intraperitoneal Chemotherapy, 3D Tumor Organoids, Organoids, HIPEC, Colorectal Cancer