Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in tumor stroma play a key role in disease progression. Recent studies using mice models suggest that CAFs are partly derived from bone marrow and TAMs primarily originate from bone marrow-derived inflammatory monocytes. However, the origin of these cells in humans remains unclear. Hence, we investigated their human origin, using specimens from human secondary tumors that developed after sex-mismatched bone marrow transplantation, by modified immunofluorescent in situ hybridization analysis and triple immunostaining. We observed that most of the alpha-smooth muscle actin (alpha SMA)-positive CAFs in the mammary gland, liver, and oral mucosa specimens obtained 3-19 years after bone marrow transplantation are recipient-derived cells. In contrast, the majority of the peritumoral alpha SMA-negative fibroblast-like cells are actually bone marrow-derived HLA-DR-positive myeloid cells, such as macrophages and dendritic cells. Furthermore, almost all CD163-positive TAMs and macrophages present in the non-tumor areas are derived from bone marrow.