Abstract
Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.
Highlights
Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types, including osteocytes, chondrocytes, adipocytes, epithelial cells and endothelial cells[1,2,3]
We identify the subpopulations of intratumoral BMSCs (T-BMSCs), which show high motility and immunosuppressive effects, and BMSCs, which move from primary tumour sites back into the bone marrow (B-BMSCs) and are associated with an stronger immunosuppressive environment
BMSCs promote lung cancer cell growth and metastasis To evaluate whether BMSCs promote cancer growth and facilitate the metastatic process of cancer cells, we constructed syngeneic tumour model that murine BMSCs and murine Lewis lung carcinoma cells (LLCs) cells were subcutaneously injected into C57BL/6 mice
Summary
Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types, including osteocytes, chondrocytes, adipocytes, epithelial cells and endothelial cells[1,2,3]. BMSCs have been extensively explored in functions of Official journal of the Cell Death Differentiation Association. Tumour-associated fibroblasts promote tumorigenesis, whereas normal fibroblasts do not show potent tumorigenesis. These properties indicate that the tumorigenesis of inflammatory fibroblasts is due to the influence of cancer cells[12,13].Tumour–stroma interactions modulate the microenvironment to be more permissive to cancer cells[14]. As well as multiple cellular elements in the microenvironment, co-evolve during the process of carcinogenesis[11]. BMSCs evolve and differentiate in cancer microenvironments[16,17]. BMSCs can differentiate into adipocytes, endothelial and fibroblasts in the cancer microenvironment[1,18]
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