ANXA1 Contained in EVs Regulates Macrophage Polarization in Tumor Microenvironment and Promotes Pancreatic Cancer Progression and Metastasis.

Nunzia Novizio,Emanuela Pessolano,Pietro Campiglia,Amelia Filippelli,Antonello Petrella,Alessandra Tosco,Raffaella Belvedere,Silvana Morello

doi:10.3390/ijms222011018

Nunzia Novizio, Emanuela Pessolano + Show 6 more

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https://doi.org/10.3390/ijms222011018

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Abstract

The tumor microenvironment (TME) is a dynamic system where nontumor and cancer cells intercommunicate through soluble factors and extracellular vesicles (EVs). The TME in pancreatic cancer (PC) is critical for its aggressiveness and the annexin A1 (ANXA1) has been identified as one of the oncogenic elements. Previously, we demonstrated that the autocrine/paracrine activities of extracellular ANXA1 depend on its presence in EVs. Here, we show that the complex ANXA1/EVs modulates the macrophage polarization further contributing to cancer progression. The EVs isolated from wild type (WT) and ANXA1 knock-out MIA PaCa-2 cells have been administrated to THP-1 macrophages finding that ANXA1 is crucial for the acquisition of a protumor M2 phenotype. The M2 macrophages activate endothelial cells and fibroblasts to induce angiogenesis and matrix degradation, respectively. We have also found a significantly increased presence of M2 macrophage in mice tumor and liver metastasis sections previously obtained by orthotopic xenografts with WT cells. Taken together, our data interestingly suggest the relevance of ANXA1 as potential diagnostic/prognostic and/or therapeutic PC marker.

Highlights

wild type (WT) extracellular vesicles (EVs) induced a high expression mainly of M2 markers compared to the treatment with IL-4 and IL-13 used as M2 controls
To confirm that the WT EVs induced the polarization of macrophages to M2 phenotype, we measured the production of the cytokine IL10 by ELISA (Figure 1C)
(M1 macrophage markers) and CD163 and CD206 (M2 macrophage markers) staining by immunofluorescence in WT and annexin A1 (ANXA1) KO mice pancreas and liver sections. (C) The histograms showed the densitometry analysis on immunofluorescence images based on the intensity of each signal compared to the total number of nuclei

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pancreatic cancer (PC) correlates to poor prognosis and high mortality due to late diagnosis, as well as early stages. Resectable PC patients have poor prognosis due to several factors such as chemoresistance by tumor microenvironment (TME) and by tumor cells per se [1]. Recent studies show that TME plays a critical role in PC progression [2,3], highlighting the strong relationship between the microenvironment and metastasis.

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