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Tumor-associated fibroblasts predominantly come from local and not circulating precursors
- Source :
- Proceedings of the National Academy of Sciences. 113:7551-7556
- Publication Year :
- 2016
- Publisher :
- Proceedings of the National Academy of Sciences, 2016.
-
Abstract
- Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP+ cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP+ cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COL-EGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I–expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
Cell type
Stromal cell
Green Fluorescent Proteins
Biology
Collagen Type I
03 medical and health sciences
0302 clinical medicine
Cancer-Associated Fibroblasts
Stroma
Cell Line, Tumor
medicine
Animals
Mice, Knockout
Tumor microenvironment
Multidisciplinary
Mesenchymal stem cell
Neoplasms, Experimental
Biological Sciences
Actins
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Bone marrow
Type I collagen
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....55fdb280aa5d1966a6788c4304199350