Introduction The UK has the highest age-standardised incidence of oesophageal adenocarcinoma (EAC) worldwide. Deaths from EAC have risen by 50% since the 1970’s and 10-year survival is 1 in 10. An activated stroma (defined by α-SMA positive, Cancer Associated Fibroblasts (CAF)) is associated with poor prognosis across tumour types. We have shown the presence of CAF to be more predictive of survival in EAC than traditional pathological markers.1Stromal targeting is a novel area in cancer treatment, no currently licensed drugs are effective in targeting CAF. We describe the repurposing of Phosphodiesterase Type 5 inhibitors (PDE5i) for use in the treatment of EAC.
Method The effect of PDE5i on EAC CAF was studied using small molecule inhibitors and siRNA knock down in primary cell culture and functional assays; collagen gel contraction, Transwell® invasion and 3D organotypic culture. Weighted correlation gene network analysis (WCGNA) was carried out on publically available gene microarray.
Results PDE5 expression was upregulated in CAF extracted from EAC patients, compared to matched normal fibroblasts (n = 3). PDE5i significantly decreased the expression of α-SMA by CAF. Functional effects were investigated and a significant decrease in collagen-1 gel contraction (p = 0.012) was observed. Cancer cell migration (p < 0.001) and invasion (p < 0.001) in response to CAF was significantly reduced by PDE5i treatment. siRNA knock down of PDE5 confirmed the effect was PDE5 mediated. WCGNA analysis reveals PDE5 expression correlates with extracellular matrix (ECM) organisation genes (including α-SMA) in EAC. Gene ontology and pathway analysis demonstrate these genes are asscoiated with muscle contraction.
Conclusion Stromal targeting by CAF inactivation is a new potential treatment for hard to treat solid organ malignancies. We have compelling evidence that PDE5i treatment of EAC CAF significantly decreases; α-SMA expression, contractility and the ability to promote cancer cell invasion. Recent evidence supports the role of CAFs in tumourigenesis and immune modulation,2,3PDE5 inhibition of the CAF phenotpye offers the possibility of increased drug deliver (chemo/immunotherapy) and host immune cell infiltration, decreased local and distant cancer growth and invasion. The time is right for the first human trial of PDE5i as an anti-cancer therapy.
Disclosure of interest None Declared.
Underwood et al. Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma. J Pathol. 2015
Han et al. Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts. Tumour Biol. 2015
Fearon, et al. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014
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