Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

Published on Dec 26, 2017in Cell Reports8.109
· DOI :10.1016/J.CELREP.2017.12.011
Daniel H. Madsen19
Estimated H-index: 19
Henrik J. Jürgensen14
Estimated H-index: 14
(UCPH: University of Copenhagen)
+ 7 AuthorsThomas H. Bugge67
Estimated H-index: 67
(NIH: National Institutes of Health)
Summary Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which collagen is fragmented by pericellular collagenases, endocytosed by collagen receptors, and routed to lysosomes for degradation by cathepsins. Here, we use intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all display vigorous endocytic collagen degradation. The cells engaged in this process are identified as tumor-associated macrophage (TAM)-like cells that degrade collagen in a mannose receptor-dependent manner. Accordingly, mannose-receptor-deficient mice display increased intratumoral collagen. Whole-transcriptome profiling uncovers a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies reveal that collagen-degrading TAMs originate from circulating CCR2+ monocytes. This study identifies a function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.
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