RESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is highly malignant with a very poor prognosis due to its silent development and metastatic profile with a 5-year survival rate below 10%. PDAC is characterised by an abundant desmoplastic stroma modulation that influences cancer development by extracellular matrix/cell interactions. Elastin is a key element of the extracellular matrix. Elastin degradation products (EDPs) regulate numerous biological processes such as cell proliferation, migration and invasion. The aim of the present study was to characterise for the first time the effect of two EDPs with consensus sequences "GxxPG" and "GxPGxGxG" (VG-6 and AG-9) on PDAC development. The ribosomal protein SA (RPSA) has been discovered recently, acting as a new receptor of EDPs on the surface of tumour cells, contributing to poor prognosis. METHODS: Six week-old female Swiss nude nu/nu (Nu(Ico)-Foxn1nu) mice were subcutaneously injected with human PDAC MIA PaCa-2/eGFP-FLuc+ cells, transduced with a purpose-made lentiviral vector, encoding green fluorescent protein (GFP) and Photinus pyralis (firefly) luciferase (FLuc). Animals were treated three times per week with AG-9 (n = 4), VG-6 (n = 5) or PBS (n = 5). The influence of EDP on PDAC was examined by multimodal imaging (bioluminescence imaging (BLI), fluorescence imaging (FLI) and magnetic resonance imaging (MRI). Tumour volumes were also measured using a caliper. Finally, immunohistology was performed at the end of the in vivo study. RESULTS: After in vitro validation of MIA PaCa-2 cells by optical imaging, we demonstrated that EDPs exacerbate tumour growth in the PDAC mouse model. While VG-6 stimulated tumour growth to some extent, AG-9 had greater impact on tumour growth. We showed that the expression of the RPSA correlates with a possible effect of EDPs in the PDAC model. Multimodal imaging allowed for longitudinal in vivo follow-up of tumour development. In all groups, we showed mature vessels ending in close vicinity of the tumour, except for the AG-9 group where mature vessels are penetrating the tumour reflecting an increase of vascularisation. CONCLUSIONS: Our results suggest that AG-9 strongly increases PDAC progression through an increase in tumour vascularisation.
