PDE5 INHIBITORS CAN AMELIORATE CHEMORESISTANCE IN OESOPHAGEAL ADENOCARCINOMA CAUSED BY CANCER-ASSOCIATED FIBROBLASTS


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Clarisa Choh1,Annette Hayden1,Ewan Kyle1,Jeremy Blaydes1,Tim Underwood1
1University of Southampton

Abstract

Background

Majority of patients who undergo neoadjuvant chemotherapy for oesophageal adenocarcinoma (OAC) do not complete treatment. For those who do, there is a low response rate of less than 40%. This is thought to be attributable to chemoresistance mediated by cancer cells and the tumour microenvironment.

Our aims were to demonstrate if cancer-associated fibroblasts (CAFs) support resistance to chemotherapy for OAC, and to determine if phosphodiesterase 5 inhibitors (PDE5i), by reverting the CAF phenotype, could increase sensitivity of oesophageal adenocarcinoma cells to chemotherapy agents.

Method

Concentration of drug required to kill 50% of cells (IC50) for chemotherapy agents used in the MAGIC and CROSS trials were individually assessed using MFD1, an oesophageal adenocarcinoma cell line. Cell viability was assessed using MTS assays. Dose-response experiments and colony forming assays (CFA) were performed using normal media, CAF-conditioned medium (CAF-CM) and medium retrieved after CAFs have been treated with Vardenafil (PDE5i) for 72 hours (V-CM). Expression of ╬▒SMA, a marker of CAF differentiation, was assessed by Western blotting to determine CAF de-differentiation after Vardenafil treatment. Colony forming assays were also performed with chemotherapy agents in normal medium and CAF-CM, and colonies were counted.

Results

IC50 of cisplatin was observed to be higher in CAF-CM than in normal media. This was reflected in CFA, whereby more colonies had formed when CAF-CM was used. A similar trend was observed with Carboplatin and 5FU.

When V-CM is used, MFD1 cells appear to be more sensitive to 5FU and carboplatin.

Conclusion

Secreted factors from CAF-CM can promote chemoresistance of MFD1 cells to cisplatin, carboplatin and 5FU.

CM from PDE5i-treated CAFs can increase sensitivity of MFD1 cells to carboplatin and 5FU.

Little response of MFD1 to other chemotherapy agents, despite a reduction in CAF differentiation with PDE5i, leads us to believe that a more complex model encompassing cell-cell contact may be required.