The immune suppressive tumour stromal cell expressing Fibroblast Activation Protein (FAP) belongs to a cellular lineage mediating essential physiological functions


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Douglas Fearon1
1Cancer Research UK Cambridge Research Institute, Cambridge, UK


Stromal cells expressing the membrane protein, FAP, were identified in human adenocarcinomas 20 years ago. FAP+ stromal cells were subsequently found in inflammatory lesions associated with autoimmunity and wound healing, and in the placenta, suggesting involvement in tissue repair and remodeling, and immune suppression. We examined the role of tumoral FAP+ cells by creating a bacterial artificial chromosome (BAC) transgenic mouse in which FAP+ cells express the diphtheria toxin receptor (DTR) to permit their conditional ablation. Depleting FAP+ cells from immunogenic, ectopic and spontaneous tumors causes rapid hypoxic necrosis that is immunologically mediated. Using another BAC transgenic mouse expressing luciferase in FAP+ cells, we have now surprisingly identified these cells in many normal tissues. We have begun to characterize FAP+ cells in adipose tissue, bone, skeletal muscle and the tumor by RNA-Seq and found that all have the “gene signature” reported for “cancer-associated fibroblasts” (Erez, et al. Cancer Cell 2010), suggesting that this signature identifies a lineage rather than a cancer-induced stromal program. Thus far, we have observed two phenotypes when depleting FAP+ cells in non-tumor-bearing mice: rapid weight loss and cessation of hematopoiesis. The former reflects the role of FAP+ cells of skeletal muscle in suppressing the ActRIIB pathway of skeletal muscle catabolism. The latter phenotype may indicate that the FAP+ cells in the endosteum of the bone marrow, which have an osteoblastic phenotype, participate in formation of the osteoblastic niche for hematopoietic stem cells. Therefore, the FAP+ stromal cell is not only a non-redundant element of immune suppression in the tumor microenvironment, but also mediates essential functions in normal tissue homeostasis that relate to certain systemic effects of cancer, such as cachexia and anemia.