Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors.

Nunzia Novizio,Antonello Petrella,Pietro Campiglia,Mauro Perretti,Emanuela Pessolano,Amalia Porta,Raffaella Belvedere,Amelia Filippelli,Alessandra Tosco

doi:10.3390/cells9122719

Nunzia Novizio, Antonello Petrella + Show 7 more

Open Access

https://doi.org/10.3390/cells9122719

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Abstract

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC.

Highlights

Pancreatic cancer (PC) remains one of the deadliest cancers worldwide, mainly due to the limited response to currently available forms of treatments, as demonstrated by the frequently reported poor clinical outcome and high mortality rate [1,2]
In order to investigate the role of Annexin A1 (ANXA1) on extracellular vesicles (EVs)-dependent metastatic potential of PC cells, we studied the paracrine effects of EVs derived by wild type (WT) and ANXA1 KO MIA PaCa-2 cells on BJ
The PC microenvironment plays a critical role in tumor progression [49], revealing a strong relationship between its organization and metastasis

Summary

Introduction

Pancreatic cancer (PC) remains one of the deadliest cancers worldwide, mainly due to the limited response to currently available forms of treatments, as demonstrated by the frequently reported poor clinical outcome and high mortality rate [1,2]. Comparative analysis of protein profiles of PC and normal pancreatic cells have already highlighted a significant over-expression of Annexin A1 (ANXA1) [3,4]. This protein retains calcium-mediated phospholipid binding properties and participates in many physiopathological processes including cell proliferation, migration, differentiation and death as well as inflammation [5,6,7]. During PC progression, it may contribute to the acquisition of a mesenchymal phenotype by tumor cells, essential for their diffusion in distant sites, suggesting that the protein may represent a potential PC diagnostic/prognostic marker [11,12]. The different functions attributed to ANXA1 are related to its subcellular localization, for example, inside the cells, ANXA1 can directly and indirectly promote the cytoskeletal organization [13,14,15]

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