Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32398
Title: The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours
Authors: Kamata, Tamihiro
Jin, Hong
Giblett, Susan
Patel, Bipin
Patel, Falguni
Foster, Charles
Pritchard, Catrin
First Published: 16-Jul-2015
Publisher: Wiley Open Access with European Molecular Biology Organization (EMBO)
Citation: EMBO Molecular Medicine, 2015, 7 (9), pp. 1119-1137
Abstract: The tumour microenvironment is known to play an integral role in facilitating cancer progression at advanced stages, but its function in some pre-cancerous lesions remains elusive. We have used the V600EBRAF-driven mouse lung model that develop premalignant lesions to understand stroma-tumour interactions during pre-cancerous development. In this model we have found that immature macrophage-lineage cells (IMCs) producing PDGFA, TGFβ and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 (CCR1)-dependent mechanisms. Stromal IMCs promote proliferation and transcriptional alterations suggestive of epithelial-mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for maintenance of early-stage lung tumours in vivo. Furthermore, we have found that IMC recruitment to the microenvironment is restrained by the cholesterol binding protein, Niemann-Pick type C2 (NPC2). Studies on isolated cells ex vivo confirm that NPC2 is secreted from tumour cells and is taken up by IMCs wherein it suppresses secretion of the CCR1 ligand CC chemokine 6 (CCL6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for development of chemopreventive strategies in lung cancer.
DOI Link: 10.15252/emmm.201404838
ISSN: 1757-4676
eISSN: 1757-4684
Links: http://embomolmed.embopress.org/content/7/9/1119
http://hdl.handle.net/2381/32398
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2015. This is an open-access article distributed under the terms of the Creative Commons Attribution- ShareAlike 4.0 International License (https://creativecommons.org/licenses/by-sa/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited, and that any contributions are distributed under the same license as the original.
Appears in Collections:Published Articles, Dept. of Biochemistry

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