Tumor-associated fibroblasts predominantly come from local and not circulating precursors.
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.
Department of Pathology, The University of Chicago, Chicago, IL 60637; Committee on Immunology, The University of Chicago, Chicago, IL 60637; aarina@bsd.uchicago.edu.
Ainhoa
A
Arina
Department of Pathology, The University of Chicago, Chicago, IL 60637; Committee on Immunology, The University of Chicago, Chicago, IL 60637;
Christian
C
Idel
Department of Pathology, The University of Chicago, Chicago, IL 60637;
Elizabeth M
EM
Hyjek
Committee on Immunology, The University of Chicago, Chicago, IL 60637; Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL 60637;
Maria-Luisa
ML
Alegre
Committee on Immunology, The University of Chicago, Chicago, IL 60637; Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL 60637;
Ying
Y
Wang
Integrated Microscopy Core, Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, IL 60637;
Vytautas P
VP
Bindokas
The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637; Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637;
Ralph R
RR
Weichselbaum
Department of Pathology, The University of Chicago, Chicago, IL 60637; Committee on Immunology, The University of Chicago, Chicago, IL 60637; Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637.
Hans
H
Schreiber
D000199:Actins / Q000378:metabolism; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000473:pathology / Q000502:physiology*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D049452:Green Fluorescent Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000473:pathology*
D000199:Actins; D024042:Collagen Type I; C544013:alpha-smooth muscle actin, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
bone marrow; collagen; mesenchymal; origin; stroma