Investigation of Molecular Mechanisms Governing Cancer Exosomes-Orchestrated Tumor-Host Interaction during Disease Progression.

The tumor-host interaction which reprograms cell plasticity and constructs tumor microenvironments for potentiating tumor initiation, local inflammation, and host cell recruitment is emerging as fundamental therapeutic targets. Exosomes known as cell-secreted microvesicles are utilized predominately for intercellular communication in between host cells and malignant counterparts at localized tumors. The abundance of exosomes in body fluids and peripheral blood suggests their functionality as distal regulatory cargos for host cell education. The stem cell populations have been implicated in cancer progression with the assistance of stromal cells in tumor microenvironment. However, mechanistic divergences and contents of eoxosmes-derived from stem cell populations in tumor bulks during cancer progression are largely unknown. In our pilot studies, we had found cancer stem cells (CSCs) enriched from both murine and human colorectal carcinoma (CRC) cell lines secreted much more miR-146a-loaded exosomes. These CSC-exosomes were detected in bone marrows of tumor-bearing mice and promoted the expansion of myeloid CD11b/Gr-1(+) cells in vitro. The distribution of CSC-exosomes in bone marrows of tumor-bearing mice further suggested potential effects of CSC-exosomes on CD11b/Gr-1(+) cells prior to their blood emergence and local recruitment. Herein, we hypothesized CSC-exosomes delivered stem cell signals locally to expand the stem cell pool first and thus, elevated serum CSC-exosome amounts to educate hosts at more distal organs for creating a tumor-permissive host environment, cumulatively. To ascertain this point, we put forth our further directions as a three-year proposal. First, we will investigate the transportation of stem cell signal to surrounding tumor cells. In the second year, we will identify intrinsic and extrinsic CSC-exosome secretion mechanisms for developing feasible therapeutic targets. Finally, we will identify CSC-exosomes-mediated host-cancer interaction and interrogate their clinical relevance. Investigations of CSC-exosomes will define feasible targets to hamper CSC-initiated malignancy, lead to the development of CSC-exosome removers for clinical application and prolong life expectancy of cancer patients.