Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia

Abstract

Ablation of stromal cells expressing fibroblast activation protein-α (FAP) results in cachexia and anemia, and loss of these cells is seen in transplantable tumor models.

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

“…Another study assessing colorectal patients receiving 131 Ilabeled anti-FAP antibody reported no uptake by normal tissues, which was interpreted as indicating that the FAP protein was absent from normal tissues (40). Therefore, it was surprising when the bioluminescent signal of BAC transgenic mice in which the fap gene controlled expression of luciferase was demonstrated in almost all tissues of the (41). FAP þ cells of skeletal muscle are the major local source of follistatin, which is required to maintain muscle mass by inhibiting myostatin and activin A signaling in this tissue.…”

“…For example, FAP þ cells are altered in skeletal muscle and the bone marrow in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia, suggesting that they may have roles in these poorly understood cancer-induced syndromes (41). Fortunately, the discovery of the FAP þ lineage and its essential homeostatic functions occurred before the consideration of depleting FAP þ cells, as a means for overcoming tumoral immune suppression had advanced to a human clinical program.…”

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 + T cells

“…We previously described a bacterial artificial chromosome (BAC) transgenic (Tg) mouse line (DM2) (21) in which the fap gene in the BAC has been modified by the insertion of a cassette composed of the coding sequences of the primate diphtheria toxin (DTX) receptor (DTR) and firefly luciferase. In this Tg mouse, fap-driven luciferase expression was detected in the inguinal LN (iLN) but not the spleen, consistent with the relative levels of Fap mRNA in these tissues (Fig.…”

“…Whereas FAP −/− mice are phenotypically indistinct from wild-type mice (18), the stromal cell that expresses FAP mediates immune suppression in the tumor microenvironment (19,20) and maintains skeletal muscle mass and hematopoiesis (21,22). FAP + stromal cells from different organs display similar gene expression profiles, but adopt organ-specific functions, like the production of specific cytokines and chemokines.…”

“…FAP + stromal cells from different organs display similar gene expression profiles, but adopt organ-specific functions, like the production of specific cytokines and chemokines. For example, FAP + stromal cells in skeletal muscle maintain muscle mass through the production of follistatin, whereas bone marrow (BM)-derived FAP + cells include CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells and support hematopoiesis by producing CXCL12, interleukin (IL)-7, and kitligand (21,23). The roles of FAP + stromal cells in other tissues and organs have not yet been defined.…”