from Nature Reviews Cancer by Gemma K. Alderton
Why do some cancers only metastasize to certain organs? This question of organotropism is perplexing, and a team led by Lyden, Bromberg and Peinado have found that exosomes could be key.
Exosomes can contribute to the pre-metastatic niche by ‘educating’ resident cells and promoting inflammation at distant sites, and thereby facilitate metastatic outgrowth. Hoshino, Costa-Silva, Shen et al. isolated and labelled exosomes from a series of cancer cell lines that metastasize to the lung (MDA-MB-231 cells) or liver (BxPC-3 and HPAF-II cells). The authors found that, on intravenous injection into nude mice, MDA-MB-231-derived exosomes were specifically over-represented in the lungs compared with exosomes from BxPC-3 and HPAF-II cells, which accumulated in the liver. Moreover, injection of exosomes from a series of MDA-MB-231-derived cell lines with different organotropic metastatic behaviours to the lung, bone or brain in nude mice further demonstrated that exosomes exhibit organotropism that corresponds to that of the cells from which they are derived.
Model of exosome-mediated organotropic tumour dissemination. Tumour-derived exosomes are uptaken by organ-specific resident cells in future metastatic organs based on integrin expression.
Next, the authors injected lung-tropic exosomes into nude mice and 3 weeks later bone-tropic cancer cells were injected into the mice (using intracardiac or tail vein injection). This ‘preconditioning’ with lung-tropic exosomes significantly increased the lung metastases of bone-tropic cells, indicating that exosomes can determine the organotropic behaviour of circulating tumour cells. To investigate how, they carried out quantitative mass spectrometry to characterize the profile of adhesion proteins in various organotropic exosomes. Six integrins were highly represented and their expression correlated with organotropic behaviour. Lung-tropic exosomes expressed integrins α6, β4 and β1; liver-tropic exosomes expressed integrins β5 and αv; brain-tropic exosomes expressed integrins β3 and αv. All of the exosomes expressed integrin α2β1, indicating that this could be a biomarker for metastatic exosomes. Interestingly, the expression profile of the exosomes did not match that of the cells from which they were derived, indicating that exosome contents are selectively packaged.