title: Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia.
abstract: Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP(+) cells, we find that they reside in most tissues of the adult mouse. FAP(+) cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP(+) cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP(+) stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia.
authors.affiliation: Department of Medicine, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, England, UK.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Roberts
authors.forename: Andrew
authors.initials: A
authors.lastname: Deonarine
authors.forename: James O
authors.initials: JO
authors.lastname: Jones
authors.forename: Alice E
authors.initials: AE
authors.lastname: Denton
authors.forename: Christine
authors.initials: C
authors.lastname: Feig
authors.forename: Scott K
authors.initials: SK
authors.lastname: Lyons
authors.forename: Marion
authors.initials: M
authors.lastname: Espeli
authors.forename: Matthew
authors.initials: M
authors.lastname: Kraman
authors.forename: Brendan
authors.initials: B
authors.lastname: McKenna
authors.forename: Richard J B
authors.initials: RJ
authors.lastname: Wells
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Rachel
authors.initials: R
authors.lastname: Larder
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Coll
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Fearon
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000740:Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases; D004920:Erythropoiesis / Q000235:genetics; D038681:Follistatin / Q000235:genetics / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics* / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics; D038041:Lymphopoiesis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D054377:Chemokine CXCL12; D010450:Endopeptidases; D038681:Follistatin; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C515256:Cxcl12 protein, mouse