Abstract
Approximately 25% of colorectal cancer (CRC) patients develop peritoneal metastasis, a condition associated with a bleak prognosis. The CRC peritoneal dissemination cascade involves the shedding of cancer cells from the primary tumor, their transport through the peritoneal cavity, their adhesion to the peritoneal mesothelial cells (PMCs) that line all peritoneal organs, and invasion of cancer cells through this mesothelial cell barrier and underlying stroma to establish new metastatic foci. Exosomes produced by cancer cells have been shown to influence many processes related to cancer progression and metastasis. In epithelial ovarian cancer these extracellular vesicles (EVs) have been shown to favor different steps of the peritoneal dissemination cascade by changing the functional phenotype of cancer cells and PMCs. Little is currently known, however, about the roles played by exosomes in the pathogenesis and peritoneal metastasis cascade of CRC and especially about the molecules that mediate their interaction and uptake by target PMCs and tumor cells. We isolated exosomes by size−exclusion chromatography from CRC cells and performed cell-adhesion assays to immobilized exosomes in the presence of blocking antibodies against surface proteins and measured the uptake of fluorescently-labelled exosomes. We report here that the interaction between integrin α5β1 on CRC cells (and PMCs) and its ligand ADAM17 on exosomes mediated the binding and uptake of CRC-derived exosomes. Furthermore, this process was negatively regulated by the expression of tetraspanin CD9 on exosomes.
Highlights
Exosomes are a type of extracellular vesicle (EV) of endocytic origin that are released by virtually all cells in multicellular organisms and carry out important intercellular communication functions through the transfer of their biomolecular cargo, which includes lipids, proteins, nucleic acids and metabolites, between the producing and the recipient/target cells [1]
We have previously described the generation of two stable lines derived from parental human colorectal adenocarcinoma Colo-320 cells: Colo-320/CD9, expressing high levels of cell surface CD9 after stable transfection; and Colo-320/ADAM17-KO, lacking expression of the metalloproteinase ADAM17/TACE after specific CRISPR/Cas9 knock-out of this enzyme [14]
Taking into account that the only adhesion molecule described to interact in trans with ADAM17 was the integrin α5β1, and that the α5 chain of this integrin was abundantly expressed on Colo-320 cells (Supplementary Figure S1) but not on exosomes (Figure 2C,D), these results strongly indicate that the Dis domain of exosomal ADAM17 was the ligand be
Summary
Exosomes are a type of extracellular vesicle (EV) of endocytic origin that are released by virtually all cells in multicellular organisms and carry out important intercellular communication functions through the transfer of their biomolecular cargo, which includes lipids, proteins, nucleic acids and metabolites, between the producing and the recipient/target cells [1]. Exosomes produced by cancer cells have been shown to influence many processes related to cancer progression and metastasis, such as tumor cell proliferation and invasion, angiogenesis, tumor microenvironment promotion and remodelling, chemotherapy resistance, and immune suppression (recently reviewed in [2,3,4]). In addition to acting as a barrier, PMCs play an active role in the pathogenesis of peritoneal metastasis by differentiating into cancer-associated fibroblasts (CAFs) through a process termed Mesothelial-to-Mesenchymal Transition (MMT), which fuels peritoneal metastasis and immune evasion (reviewed in [5]). Cancer-derived exosomes in malignant ascites interact with cancer cells promoting their survival, migration and invasion capacities, and with PMCs inducing their apoptosis, disrupting the mesothelial barrier and reprogramming them into CAFs through MMT. The molecules that mediate the interactions between cancer-derived exosomes and their target PMCs and tumor cells mostly remain obscure
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