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

Abstract

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 α-smooth muscle actin (αSMA)-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 αSMA-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.

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

“…As the most abundant cell type of the tumor microenvironment, CAF support multiple aspects of tumor development and growth by suppression of antitumor immune responses and by remodeling the TME in favor of tumor expansion [ 21 , 22 , 23 , 24 ]. Albeit CAF represent a heterogenous cell population of activated (myo-)fibroblasts, they are thought to derive from a variety of different sources, including hepatic stellate cells (HSC, the liver sinusoidal pericytes), (vascular) fibroblasts but to a minor degree also endothelial cells and bone marrow-derived precursors [ 25 , 26 ]. In a mouse model of inflammation-dependent gastric dysplasia, bone marrow-derived mesenchymal stem cells were recruited to the dysplastic stomach and contributed to ~25% of α-SMA + CAF [ 27 ].…”

The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

“…Activated fibroblasts are present in most mesothelioma tissues (33) and are identified by alpha smooth muscle actin (SMA). Although not studied in mesothelioma, two separate origins of cancer-associated fibroblasts and fibrocytes have been described: α-SMA expressing fibroblasts are tissue-derived, but fibrocytes with spindle-shaped nuclei are derived from macrophages or dendritic cells (α-SMA-, HLA-DR+ with moderate expression of CD68) (Figure 1) (34). Mouse models suggest that fibrocytes migrate to areas of hypoxia under the influence of CXCL12 and CXCR4 (35).…”

Immunological Consequences of Nanoparticle‐Mediated Antitumor Photoimmunotherapy

“…Current therapeutic strategies mainly include radiotherapy, chemotherapy, surgery, and phototherapies. Most of the time, surgery alone is not able to completely eradicate the tumor and also induce an immunosuppressive effect to impair the function of T‐lymphocytes and NK‐cells . Although chemotherapeutics and radiotherapies are well known to have an immunostimulatory effect, however, the therapeutic efficacy of radiotherapy is often limited by non‐specificity to tumor cells, systematic tumor progression, tumor‐radio resistance and distant metastases .…”