Circulating Exosomes as Diagnostic/Prognostic Indicators and Therapeutic Targets of Tumor Metastasis

Exosomes are small membrane vesicles released from the luminal membrane of multivesicular bodies by fusion with the cell membrane. Bone marrow-derived cells (BMDCs) are crucial for the generation of a suitable microenvironment for the development of metastasis through a process called pre-metastatic niche formation. This invention identified tumor-derived exosomes as new factors that promote metastatic niche formation by educating BMDCs.

Cornell inventors discovered exosome protein concentrations were higher in patients with stage IV melanoma. TYRP2, VLA-4, HSP70 and the oncoprotein MET were increased in stage IV melanoma. TYRP2 and MET were also increased in stage III melanoma. Exosomal TYRP2 predicts disease progression in patients with stage III melanoma. The expression of these proteins can serve as an exosome-specific melanoma signature with prognostic and therapeutic potential.

Tumor exosomes increased metastatic burden and tissue distribution by educating bone marrow derived cells. Exosome-mediated transfer of oncogene Met was partially responsible for increased Met expression in bone marrow progenitor cells. Bone marrow cells treated with exosomes with decreased Met expression showed decreased pro-angiogenic bone marrow progenitor cells, c-Kit+, Tie2+ cells.

The inventors also investigated the expression of Ras-related RAB genes as RAB proteins control exosome biogenesis. Knockdown experiments demonstrated that decreased Rab27a expression reduced exosome production and circulating exosome concentrations, which prevented the recruitment of the BMDCs that were necessary for metastatic progression.

Potential Applications

• Targeting primary cancer cell exosomes to inhibit metastatic disease progress;
• Targeting RAB gene to reduce tumor exosome production;
• Predicting outcome and diagnosing a subject having cancer by measuring the circulating levels of exosomes and levels of their signature proteins;
• Screening candidate compounds that inhibit tumor growth or the formation and progression of metastatic disease

Advantages

• New markers and targets for predicting, diagnosing and treating tumor metastasis
• Markers of tumor metastasis to diagnose melanoma (at all stages), instead of the more traditional physical examination