Extracellular Vesicles in Colorectal Cancer: Mediators of tumor aggressiveness

Extracellular vesicles (EVs) are small vesicles released from cells. EVs represent an important mode of intercellular communication by serving as vehicles for transfer of proteins and nucleic acids between cells. Interestingly, the exosome composition differs in healthy and diseased individuals, making these vesicles attractive as a non-invasive source of biomarkers. The aims of this thesis were to i) analyze the miRNA-cargo of EVs from hypoxic CRC cell lines and investigate their impact on tumor aggressiveness and resistance to therapy in rectal cancer patients, ii) identify plasma exosomal miRNAs associated with rectal cancer aggressiveness and outcome, iii) and investigate the modulatory role of cancer derived EVs on immune cells. Well established CRC-cell lines and primary monocytes isolated from healthy individuals were used for the in vitro studies, and plasma samples were collected from patients with locally advanced rectal cancer involved in the OxyTarget study and LARC-RRP study. We observed a cell-line specific profile of exosomal miRNAs regulated by hypoxia in vitro where three miRNAs were differentially expressed in the circulation of patients with high-risk and aggressive rectal cancer. Furthermore, we investigated baseline characteristics of rectal cancer patients and identified two exosomal miRNAs predictive of metastasis in two cohorts. Finally, functional studies of EV-uptake and responses by monocytes supported that CRC-derived EVs could be mediators of immune responses by regulating monocyte gene transcription and cytokine release. Overall, the results contribute to increased knowledge of the cargo and functional role of CRC-derived EVs. Vesicle-associated differences in miRNA expressions can serve as markers for tumor hypoxia and metastasis, however, the findings must be validated in larger patient cohorts