Author:
Arina Ainhoa,Idel Christian,Hyjek Elizabeth M.,Alegre Maria-Luisa,Wang Ying,Bindokas Vytautas P.,Weichselbaum Ralph R.,Schreiber Hans
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.
Funder
HHS | National Institutes of Health
Publisher
Proceedings of the National Academy of Sciences
Reference68 articles.
1. Metchnikoff E (1892) Leçons sur la pathologie comparée de l’inflammation. Faites à l’Institut Pasteur en Avril et Mai 1891 (Masson, Paris).
2. Culture of blood leukocytes. From lymphocytes and monocytes to connective tissue;Maximov;Arch Exp Zellforsch,1928
3. Stromal-hematopoietic interrelationships: Maximov’s ideas and modern models;Friedenstein;Haematol Blood Transfus,1989
4. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair;Bucala;Mol Med,1994
5. Cystic fibrosis: production of high levels of uromodulin-like protein by HLA-DR blood monocytes differentiating towards a fibroblastic phenotype
Cited by
132 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献