Prepping the premetastatic niche

Sci. Signal.  23 Aug 2016:
Vol. 9, Issue 442, pp. ec191
DOI: 10.1126/scisignal.aai8394

The cargo transported in exosomes, a type of extracellular vesicle that is shed from cells, alters stromal cell activity in the tumor microenvironment to support tumor growth and drug resistance. Chronic inflammation supports tumor development and progression. Liu et al. (see also Kenific et al.) found that exosomes from primary tumor cells mediate long-range induction of inflammation in the lung, which promotes metastatic colonization. Exosomes that were collected from the serum and lung tissues of wild-type mice with or without subcutaneous melanoma or lung cancer xenografts, fluorescently labeled, and then injected into mice were taken up by alveolar type II (AT-II) epithelial cells in the lung. Injection of tumor-derived exosomes into mice induced the expression of chemokine-encoding genes in AT-II cells and increased neutrophil recruitment into the lung. RNase blocked the exosome-induced gene induction in cultured AT-II cells. RNA sequencing revealed that the cargo of exosomes isolated from xenografted mice was enriched in noncoding transcripts called small nuclear RNAs (snRNAs). The stem loops of snRNAs form double-stranded RNAs that can activate the innate immunity–associated molecule Toll-like receptor 3 (TLR3). Tumor-derived exosomes increased the abundance of TLR3 and the activation of TLR3 pathway proteins in AT-II epithelial cells. Knocking out Tlr3 in xenografted mice decreased the incidence of lung lesions, reduced the recruitment of neutrophils into the lung, and decreased the expression of genes encoding chemokines and other prometastatic factors in the lung. Bioinformatic and immunohistochemical analyses revealed that non–small cell lung carcinoma patients with a high abundance of TLR3 in adjacent lung epithelial tissue had a high amount of neutrophil infiltration and poor prognosis. The findings suggest that targeting TLR3 might suppress localized spread in lung cancer patients and distant lung metastasis in melanoma patients.

Y. Liu, Y. Gu, Y. Han, Q. Zhang, Z. Jiang, X. Zhang, B. Huang, X. Xu, J. Zheng, X. Cao, Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016). [PubMed]

C. M. Kenific, L. Nogués, D. Lyden, Pre-metastatic niche formation has taken its TOLL. Cancer Cell 30, 189–191 (2016). [PubMed]