Cells undergo competitive interactions as a homeostatic mechanism that enables the elimination of damaged cells and ensures appropriate cell number in a limited niche. Noting that noncancerous cells can inhibit the growth of co-cultured cancer cells, and that cancer cells can be deficient in tumor-suppressive microRNAs (miRNAs), Kosaka et al. explored the possibility that nonmalignant cells might restrain the proliferation of neighboring cancer cells by secreting such miRNAs. Medium in which the noncancerous prostate cancer cell line PNT-2 had grown (PNT-2 CM) inhibited the proliferation of a hormone-insensitive prostate cancer cell line (PC-3M-luc), whereas medium in which the cancer cells themselves had grown did not. MiRNAs can be secreted in small ceramide-rich vesicles known as exosomes, through a process that depends on neutral sphingomyelinase 2. Various approaches indicated that exosomes secreted by PNT-2 cells were incorporated into PC-3M-luc cells and mediated the antiproliferative message. These included co-culture analyses in which the PNT-2 cells had been preincubated with a fluorescent BODIPY-ceramide dye, exposure of PC-3M-luc cells to a fluorescently labeled exosomal fraction of PNT-2 CM, and treatment of PNT-2 cells with the neutral sphingomyelinase 2 inhibitor GW4869. The intracellular and extracellular abundance of multiple miRNAs, including miR-143, was decreased in PC-3M-luc compared with PNT-2 cells; moreover, GW4869 suppressed miR-143 secretion from PNT-2 cells. The proliferation of PC-3M-luc cells exposed to CM from miR-143–overexpressing HEK293 cells was decreased compared to those treated with CM from control HEK293 cells; moreover, PC-3M-luc cells exposed to CM from the miR-143–overexpressing HEK293 cells showed increased miR-143 abundance and decreased abundance of the miR-143 target KRAS. Indeed, compared with CM from control HEK293 cells, local injection of CM from the miR-143–overexpressing HEK293 cells suppressed the growth of PC-3M-luc cell–derived tumors in nude mice and decreased the abundance of the kinases KRAS and ERK5 in the tumors. The authors thus conclude that exosomal secretion of miRNAs from noncancerous cells can inhibit cancer cell proliferation.
N. Kosaka, H. Iguchi, Y. Yoshioka, K. Hagiwara, F. Takeshita, T. Ochiya, Competitive interactions of cancer cells and normal cells via secretory microRNAs. J. Biol. Chem. 287, 1397–1405 (2012). [Abstract] [Full Text]