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

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.

Secretome from In Vitro Mechanically Loaded Myoblasts Induces Tenocyte Migration, Transition to a Fibroblastic Phenotype and Suppression of Collagen Production

“…Another study showed that PDGF induced a migration response at concentrations of 1–5 ng/mL, while at higher concentrations (>5 ng/mL), PDGF induced proliferation but not migration of NIH3T3 fibroblasts [ 56 ]. Additionally, Toti et al showed that microvesicles-mediated transfer of Galectin-1 proteins from fibroblasts stimulates cell migration [ 57 ]. These studies suggest that the concentration of cytokines as well as specific proteins in the secretome from myoblasts lead to different outcomes on cell migration and proliferation.…”

Cancer-associated fibroblasts subtypes and role in invasion and metastasis of gastric cancer

“…Besides, a proteomic analysis of human breast cancer tissues revealed that galectin-1 is upregulated in cancer-associated stroma tissue. And natriuretic peptide B (NPPB), increasing in ovarian cancer stroma compared with normal ovarian stroma, also has been identified as a potential candidate marker for CAFs [16,17].…”

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives

“…The interactions in the tumor microenvironment are considered another critical mechanism for cancer progression that assimilate peripheral cells through secretion of various molecules [ 133 , 134 ]. Furthermore, there are various cells surrounding the microenvironment, such as stromal cells and immune cells, which are reportedly regulated by Gals [ 82 , 135 , 136 ]. Additionally, immune evasion is one of the most important mechanisms for cancer survival [ 137 ].…”

“…In contrast, Higareda-Almaraz and coworkers showed that Gal-7 is a negative regulator of cervical cancer that acts through reprogramming the tumor microenvironment [ 78 ]. Interestingly, fibroblasts were shown to be activated by cancer cells known as cancer-associated fibroblasts, and the expression of Gals was associated with fibroblast activation and promoted growth [ 135 , 136 ]. Toti et al found that knockdown of Gal-1 in tumor stromal cells, such as human pancreatic stellate cells, decreased pancreatic ductal adenocarcinoma growth in vivo [ 97 ].…”

“…Toti et al found that knockdown of Gal-1 in tumor stromal cells, such as human pancreatic stellate cells, decreased pancreatic ductal adenocarcinoma growth in vivo [ 97 ]. In addition, cancer-associated fibroblasts mediate Gal-1 regulation of cancer cell motility through macrovesicle release, and knockdown of Gal-1 prevents cancer-associated fibroblast-mediated prostate and pancreatic cancer migration [ 136 ]. This finding is in agreement with previously described cancer-associated fibroblasts expressing Gal-1 to promote melanoma cell migration [ 154 ].…”