5-fluorouracil treatment of patient-derived scaffolds from colorectal cancer reveal clinically critical information

Abstract

Background Colorectal cancer is a commonly diagnosed cancer worldwide. Unfortunately, many patients do not respond to standard chemotherapy treatments and develop disease relapse and metastases. Besides cancer cell specific genetic changes, heterogeneity in the tumor microenvironment contribute to the clinical presentation of the disease and can potentially also influence drug resistance. By using a recently developed patient-derived scaffold method monitoring how a standardized reporter cancer cell line adapts to various microenvironments treated with chemotherapy, we wanted to clarify how individual patient specific microenvironments influence the chemotherapy response in colorectal cancer. Methods Surgically resected colorectal cancer specimens from 89 patients were decellularized to produce patient-derived scaffold, which were seeded with HT29 cells, cultured for 3 weeks, and treated with 5-fluorouracil. Gene expression changes of adapted and treated HT29 cells were monitored by qPCR and compared with clinical parameters including disease-free survival. Results The effects of 5-fluorouracil treatment varied between different patient-derived scaffold, but generally induced a reduced expression of proliferation genes and increased expression of pluripotency and epithelial-to-mesenchymal transition genes. Interestingly, patient-derived scaffold cultures obtained from patients with disease recurrences showed a significantly less pronounced anti-proliferative effect of 5-fluorouracil and more pronounced increase of pluripotency, with MKI67 and POU5F1 being among the most significant genes linked to disease relapse in colorectal cancer. Conclusions Colorectal patient-derived scaffold can decode clinically relevant tumor microenvironmental influence of 5-fluorouracil treatment effects opening up for optimized precision medicine in colorectal cancer treatment.

Proteomics of cell‐free breast cancer scaffolds identify clinically relevant imprinted proteins and cancer‐progressing properties

“…The PDS method has earlier been shown to maintain tumor tissue heterogeniety in vitro, producing quantitative assessments of the activity of the TME when studying cancer cell lines adapted to various PDS-based cell cultures [2]. Specific gene changes in the cancer population induced by the heterogenous PDS culture conditions have also been linked to clinical observations, validating the selected strategy for this study [2][3][4][5].…”

In Vitro Assessment of the Synergistic Effect of Aspirin and 5-Fluorouracil in Colorectal Adenocarcinoma Cells

“…Furthermore, when the compounds were associated, the cytotoxic effect was enhanced, with approximately 13% of the cells remaining viable. A thorough review of the literature in the field led to the selection of the concentrations of 5-FU used in this study [51][52][53]. A study conducted by Srimuangwong et al assessed the effects of 5-FU at doses between 5 and 25 µmol/L on HT-29 cells, and it was found that the concentration of 25 µmol/L resulted in a reduction in viability below 80% after 48 h [54].…”

Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin–Progranulin Axis in Breast Cancer

“…The data illustrating that IL-6, IL-8 and the receptors sortilin, IL-6R and IL-6-ST were highly secreted from PDS-adapted breast cancer cell lines support the fact that the PDS model includes a microenvironment promoting the cancer stem cell population. In addition, the PDS model could provide information on patients with an IL-6-and progranulin-inducing microenvironment that could benefit from anti-sortilin therapy [27,[55][56][57][58][59].…”