부산대학교 도서관

Communication between cancer cells and the microenvironment is a complex yet crucial issue in disease progression. Recent studies highlight an important role for small extracellular vesicles (exosomes) secreted by cancer cells, as modulators of cancer-associated stroma, angiogenesis and metastatic priming. The intrinsic factors regulating exosome biogenesis and secretion in cancer cells are, therefore, highly relevant in studies of cross-communication in the cancer milieu. We generated prostate cancer cells bearing stable knockdown of putative exosome-regulating factors (CD9, Rab5a, Rab11b, Rab35, VAMP7 and VPS25); and examined the impact on cell health, vesicle secretion and on communication with fibroblastic stromal cells. We highlight that Rab11b or Rab35 regulate phenotypically distinct exosome subpopulations each accounting for only around 20% of the total. Depleting Rab11b or Rab35 leaves a vesicle population insufficient for driving fibroblast to myofibroblast differentiation, leading to diminished angiogenesis and attenuated invasive behaviours in 3D in vitro models. Correcting for differences in vesicle quantity revealed that perturbed differentiation due to loss of Rab11b-dependent vesicles, could be restored by normalising quantity. This, however, was not the case for Rab35-dependent vesicles. Co-implantation of tumour cells with stromal fibroblasts in xenografts similarly showed that Rab11b knockdown had little effect on growth rates in vivo. In contrast, significant attenuation was evident when using Rab35-knockdown cells. The study concludes that a Rab35 regulated exosome sub-population is particularly important for communication between cancer and stromal cells; and is required for generating a microenvironment conducive for disease promotion.