Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression

Abstract

Cholangiocarcinoma (CCA), a common primary malignant tumor of bile duct epithelia, is highly prevalent in Asian countries and unresponsive to chemotherapeutic drugs. Thus, a newly recognized biological entity for early diagnosis and treatment is highly needed. Exosomes are small membrane bound vesicles found in body fluids and released by most cell types including cancer cells. The vesicles contain specific subset of proteins and nucleic acids corresponding to cell types and play essential roles in pathophysiological processes. The present study aimed to assess the protein profiles of CCA-derived exosomes and their potential roles. We have isolated exosomes from CCA cells namely KKU-M213 and KKU-100 derived from Thai patients and their roles were investigated by incubation with normal human cholangiocyte (H69) cells. Exosomes were internalized into H69 cells and had no effects on viability or proliferation of the host cells. Interestingly, the exosomes from KKU-M213 cells only induced migration and invasion of H69 cells. Proteomic analysis of the exosomes from KKU-M213 cells disclosed multiple cancer related proteins that are not present in H69 exosomes. Consistent with the protein profile, treatment with KKU-M213 exosomes induced β-catenin and reduced E-cadherin expressions in H69 cells. Collectively, our results suggest that a direct cell-to-cell transfer of oncogenic proteins via exosomal pathway may be a novel mechanism for CCA progression and metastasis.

Exosomes in liver pathology

“…Similar results are also observed in studies with cholangiocarcinoma (CCA). A study using CCA cells derived from human patients were shown to secrete exosomes that increased migration and invasion of human cholangiocyte cell line H69 [20]. The exposure of mesenchymal stem cells to CCA cell-derived exosomes enhance their migratory capability and the release of cytokines such as CXCL1, CCL2 and IL-6 leading to cell proliferation [21].…”

Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

“…In particular, CCA‐derived EV were shown to stimulate secretion of the proinflammatory cytokine interleukin‐6 by mesenchymal stem cells, further promoting the growth of CCA cells . CCA‐derived EV also stimulate the invasion and migration of these cancer cells . Moreover, EV participate in the trafficking of specific microRNA species between cancer‐associated fibroblasts and CCA cells, thus regulating tumor growth .…”

Exosomes as Reconfigurable Therapeutic Systems

“…The endocytic origin includes endosomal proteins involved in transport and fusion (annexins and flotillin), cell targeting (tetraspanins), multi-vesicular body (MVB) proteins (Alix and TSG101) [2], as well as various proteins linked to lipid metabolism [3]. Extracellular matrix and cell surface proteins such as collagens, integrins, and galectins [4], cell surface receptors and signaling molecules, intracellular cytoskeletal components, as well as metabolic enzymes and G proteins are also present [5]. In contrast to their cells of origin, exosomes are enriched in cholesterol, ceramide, phosphoglycerides, and long and saturated fatty-acyl chains, all of which may provide structural stability [2].…”