The role of Cancer-associated fibroblasts in chemoresistance in oesophageal adenocarcinoma

Abstract

Oesophageal cancer is the fastest rising cancer in the UK, being the 5th most common cause of cancer death and associated with a low 5-year survival of 15%. 39% of patients diagnosed with oesophageal cancer have a curative management plan, half of which undergo neoadjuvant chemotherapy and surgery. Despite 70% of this cohort of patients completing chemotherapy treatment, tumour response was observed in less than 40%. This was thought to be attributable to the close relationship within the stroma and the cancer cells, which may affect the resistance of cancer cells to chemotherapy. This thesis aims to explore the role of cancer-associated fibroblasts (CAFs) in oesophageal adenocarcinoma, and its relation to chemoresistance.

Chemoresistance was characterized by using chemotherapy response in oesophageal adenocarcinoma cell lines as a surrogate marker. The role of CAFs in influencing chemoresistance was investigated with CAF-conditioned medium, and spheroidal co-cultures as a form of 3D modelling. Subsequently, phosphodiesterase-5 inhibitors (PDE5i), which had been reported to de-activate CAFs, were used on CAFs to determine if oesophageal adenocarcinoma cells could be re-sensitised to chemotherapy after treatment. Biomarkers specific to CAFs were then examined for its association with survival and to determine its relation to prediction of response to chemotherapy.

Colony growth assays demonstrated a positive effect when oesophageal adenocarcinoma cells were placed in CAF-conditioned media, together with higher drug concentrations required in dose-response assays, both of which were remediated with PDE5i treatment. When used in spheroids, there appeared to be some enhanced metabolic activity when both types of cells were in combination, and activity reduction with PDE5i treatment.

In conclusion, CAFs appear to be involved in influencing chemoresistance in oesophageal adenocarcinoma, and that PDE5i treatment seem to re-sensitize cancer cells to chemotherapy and thereby require a lower drug concentration for a cytotoxic effect. Tumour stage and presence of a biomarker such as nestin in cancerous lymph nodes correlated with a poor survival outcome, and could be considered a viable prognostic marker that can be utilized in the future.

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Identifiers

ORCID for Timothy Underwood: orcid.org/0000-0001-9455-2188

ORCID for Jeremy Blaydes: orcid.org/0000-0001-8525-0209

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