Department of Medicine, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, England, UK.
J Exp Med. 2013 Jun 3;210(6):1137-51. doi: 10.1084/jem.20122344. Epub 2013 May 27.
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.
成纤维细胞激活蛋白-α（FAP）可识别人类癌症和慢性炎症病变中的间充质来源的基质细胞。在癌症的小鼠模型中，它们被证明具有免疫抑制作用，但对其在正常组织中的发生和功能的研究却很有限。我们利用一种可使 FAP（+）细胞进行生物发光成像的转基因小鼠系，发现它们存在于成年小鼠的大多数组织中。来自三个部位（骨骼肌、脂肪组织和胰腺）的 FAP（+）细胞具有高度相似的转录组，表明它们具有共同的谱系。骨骼肌中的 FAP（+）细胞是卵泡抑素的主要局部来源，在骨髓中，它们表达 Cxcl12 和 KitL。这些细胞的实验性消融会导致肌肉质量的丧失以及 B 淋巴细胞生成和红细胞生成减少，从而分别揭示了它们在维持正常肌肉质量和造血功能中的重要作用。值得注意的是，在癌症诱导的恶病质和贫血的可移植和自发性小鼠模型中，这些部位的 FAP（+）基质细胞发生了改变。因此，FAP（+）基质细胞可能在癌症的两种不良后果中发挥作用：肿瘤获得它们可能导致免疫监视失败，而它们在正常组织中的改变则导致恶病质和贫血等副肿瘤综合征的发生。
