Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation

Abstract

Exosomes play important roles in cell-cell communication, and are likely mediators of the metastatic cascade in cancer. This study examined the role of exosomes in pancreatic cancer cell adhesion, migration, and invasion. We isolated and purified exosomes from two isogenic pancreatic cancer cell lines with different metastatic potentials. Uptake of exosomes from highly metastatic Panc02-H7 cells decreased adhesion and increased migration and invasion capacity in weakly metastatic Panc02 cells in vitro. Exosomes from highly metastatic pancreatic cancer cells induced liver pre-metastatic niche formation in naïve mice and promoted primary tumor growth and liver metastasis in vivo. We identified 4,517 proteins in exosomes from Panc02 and Panc02-H7 cells via iTRAQ quantitative proteomic analyses, 79 of which were differentially expressed between the two cell lines. Bioinformatics analyses showed that most of the differentially expressed proteins were involved in pancreatic cancer growth, invasion, and metastasis, and that metabolism-related signaling pathways were involved in exosome-mediated intracellular communication. Further studies will be needed to determine whether these proteins are potential pancreatic cancer diagnostic/prognostic markers or novel therapeutic targets.

Decoding the role of extracellular vesicles in liver diseases

“…For example, EVs derived from pancreatic ductal adenocarcinoma cells can induce pre-metastatic niche formation in the liver and facilitate cancer metastasis to the liver, which is associated with an increase in macrophage migration inhibitory factor (MIF) in exosomes. 58,59 Consistently, MIF depletion prevents pre-metastatic niche formation in the liver. 59 Recently, epidermal growth factor receptor (EGFR)-containing exosomes derived from gastric cancer cells have been shown to promote liver-specific metastasis through the suppression of miR-26a/b and subsequent activation of hepatocyte growth factor in the liver.…”

“…58–60 The roles of EVs in hepatocellular carcinoma (HCC) formation and tumor growth have been extensively investigated. HCC cells appear to secret more EVs compared with non-cancer cells.…”

Extracellular vesicles: Future diagnostic and therapeutic tools for liver disease and regeneration

“…Furthermore, Panc02‐H7‐derived EV facilitated the metastatic development of mouse pancreatic ductal adenocarcinoma (Panc02‐H7) cells to the liver . Administration of these EV 1 week before the implantation of Panc02 cells in immunocompetent mice resulted in local attraction of CD11b+/CD45+ hematopoietic progenitor cells and increased α‐SMA‐positive HSC.…”

“…Administration of these EV 1 week before the implantation of Panc02 cells in immunocompetent mice resulted in local attraction of CD11b+/CD45+ hematopoietic progenitor cells and increased α‐SMA‐positive HSC. The authors suggest that Panc02‐H7 cell‐derived EV favoured metastasis by creating a niche for the implantation of Pan02‐H7 cells …”

Unraveling the journey of cancer stem cells from origin to metastasis

“…Exosomes, small extracellular vesicles released by cells, carry cellular components to distant organs, thereby increasing cellular communications [12]. Recent studies have shown that the exosomes released by cancer cells within a primary tumor travel to distant organs and form a pre-metastatic niche [12,13]. However, it is not known which cell type in a heterogeneous primary tumor releases the exosomes with the capacity to form a pre-metastatic niche in distant organs.…”