Activated fibroblasts enhance cancer cell migration by microvesicles-mediated transfer of Galectin-1

Alessandra Toti,Elisa Pardella,Anna Caselli,Paolo Paoli,Paolo Cirri,Richard Tomasini,Alice Santi,Ilaria Nesi,Tommaso Mello

doi:10.1007/s12079-021-00624-4

Abstract

Cancer-associated fibroblasts (CAFs) are one of the main components of the stromal compartment in the tumor microenvironment (TME) and the crosstalk between CAFs and cancer cells is essential for tumor progression and aggressiveness. Cancer cells mediate an activation process, converting normal fibroblasts into CAFs, that are characterized by modified expression of many proteins and increased production and release of microvesicles (MVs), extracellular vesicles generated by outwards budding from the cell membrane. Recent evidence underlined that the uptake of CAF-derived MVs changes the overall protein content of tumor cells. In this paper, we demonstrate that tumor activated fibroblasts overexpress Galectin-1 (Gal-1) and consequently release MVs containing increased levels of this protein. The uptake of Gal-1 enriched MVs by tumor cells leads to the upregulation of its intracellular concentration, that strongly affects cancer cell migration, while neither proliferation nor adhesion are altered. Accordingly, tumor cells co-cultured with fibroblasts silenced for Gal-1 have a reduced migratory ability. The present work reveals the key role of an exogenous protein, Gal-1, derived from activated fibroblasts, in cancer progression, and contributes to clarify the importance of MVs-mediated protein trafficking in regulating tumor-stroma crosstalk.

Highlights

Tumor progression is dependent on cancer cell genetic and epigenetic alterations but it is strongly supported by the tumor reactive stroma (Valkenburg et al 2018)
One of the most important consequences of fibroblast activation is the increase in their ability to produce and secrete MVs, which are uploaded in cancer cells, thereby playing an essential role in sustaining their proliferation
We previously identified various proteins that are transferred from cancer-associated fibroblasts (CAFs) to cancer cells using MVs as vehicle (Santi et al 2015)

Summary

Introduction

Tumor progression is dependent on cancer cell genetic and epigenetic alterations but it is strongly supported by the tumor reactive stroma (Valkenburg et al 2018). Tumor mass is a complex network of cancer and stromal cells, of whose fibroblasts represent the main component. Upon stimulation by tumor cells, fibroblasts engage a trans-differentiation program converting them into their activated form, known as cancer-associated fibroblasts (CAFs) (Kalluri 2016). The tumor-stroma crosstalk is mainly mediated by soluble paracrine factors, cell–cell contacts and extracellular vesicles (EVs) trafficking (van Niel et al 2018). The specific composition of the EV content strictly depends on the cell type, the stimuli and molecular mechanisms regulating their biogenesis and release, and the physio-pathological state of the donor cells. Once released in the extracellular space, EVs target recipient cells and deliver their content which alters the phenotypical and functional properties of the targeted cells (van Niel et al 2018)

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Conclusion