Horizontal transfer of MET from exosomes to bone marrow progenitors enhances metastasis.

  • Major finding: Horizontal transfer of MET from exosomes to bone marrow progenitors enhances metastasis.

  • Clinical relevance: MET expression in circulating exosomes may be a biomarker of metastatic disease.

  • Impact: Tumor-derived exosomes can contribute to formation of the premetastatic niche.

Exosomes are membrane-derived microvesicles constitutively released by cells thought to play important roles in cell communication, signaling, immunomodulation, and tumorigenesis through the horizontal transfer of mRNAs, microRNAs, and proteins. Peinado and colleagues observed that treatment of mice with tumor-derived exosomes increased both the metastatic burden and the number of sites of metastatic disease in association with enhanced endothelial permeability and expression of inflammation and extracellular matrix remodeling genes. Exosome administration also enhanced the mobilization of bone marrow–derived provasculogenic progenitor cells. Transplantation of this exosome-educated bone marrow into recipient tumor-bearing mice stimulated recruitment of bone marrow–derived cells required for premetastatic niche formation to both the primary tumor and metastatic sites. Proteomic profiling revealed that metastatic murine melanoma-derived exosomes specifically expressed high levels of MET, and treatment of bone marrow cells with tumor-derived exosomes led to a 6-fold increase in MET-positive bone marrow progenitors. In contrast, exosomes isolated from melanoma cells in which MET had been knocked down no longer stimulated an increase in MET-positive bone marrow progenitors or metastasis when injected into tumor-bearing mice. Consistent with a role for exosome-packaged MET in metastatic disease, higher amounts of MET were found in circulating exosomes and hematopoietic progenitor cells isolated from patients with late-stage melanoma compared with healthy control subjects. Furthermore, exosome protein content and concentration were both predictive of progression of disease and poorer outcome. Collectively, these findings suggest that circulating tumor-derived exosomes directly promote cancer progression by delivering oncogenic cargo, such as the MET oncoprotein, from the primary tumor to bone marrow progenitors to facilitate establishment of premetastatic sites, enhancing the metastatic tumor burden and distribution in target tissues.

Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883–91.

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