期刊
CELL REPORTS
卷 21, 期 13, 页码 3662-3671出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.12.011
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资金
- NIDCR Intramural Research Program [Z01DE0699-05]
- European Commission/Marie Curie Program [659994]
- Danish Cancer Society [R124-A7599-15-S2, R90-A5989-B526]
- Region Hovedstadens Forskningsfond [R144-A5439]
- Novo Nordisk Foundation [NNF16OC0022922, NNF16OC0020796]
- Danish Council for Independent Research [4002-00370, 4092-00387B]
- NIDCR Veterinary Research Core and Combined Technical Research Core [DE000729-08, DE000740-05]
- Lundbeck Foundation [R118-2012-11578] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0022922] Funding Source: researchfish
- The Danish Cancer Society [R124-A7599, R90-A5823, R90-A5989, R149-A9768, R146-A9326] Funding Source: researchfish
- Villum Fonden [00007292] Funding Source: researchfish
- Marie Curie Actions (MSCA) [659994] Funding Source: Marie Curie Actions (MSCA)
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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