An expanding body of research has emphasized the involvement of small extracellular vesicles (sEVs), particularly exosomes, in colorectal cancer (CRC). Despite this, information regarding the prognostic or clinical relevance of molecules involved in sEV production in CRC remains scarce. In this project, we examined the expression patterns of key genes governing sEV formation and explored how these relate to plasma sEV quantities—measured with a double-sandwich ELISA—as well as clinical outcomes in CRC patients. Our findings indicate that mRNA levels of RAB27A, RAB27B, RAB2B, and RAB3B were significantly reduced in tumor samples when compared with adjacent non-cancerous tissues (p < 0.001, p = 0.009, p = 0.011, and p < 0.001, respectively). Moreover, elevated tumor expression of RAB27A, RAB27B, RAB9A, RAB11B, and STX1A corresponded with improved 5-year survival (p = 0.038, p = 0.015, p = 0.008, p = 0.002, and p = 0.028, respectively). Patients with adenomas also exhibited lower total plasma sEV levels than healthy controls (p = 0.026). However, CRC patients showed no significant differences in either total or tumor-originating sEV concentrations (p = 0.885 and p = 0.330, respectively). Overall, our results suggest that sEV biogenesis may play an important role in CRC progression, with RAB27A, RAB27B, RAB9A, RAB11B, and STX1A emerging as potential markers of survival.
