Int J Med Sci 2018; 15(12):1406-1414. doi:10.7150/ijms.24370

Research Paper

Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis

Hotaka Kawai1✉, Hidetsugu Tsujigiwa2, Chong Huat Siar3, Keisuke Nakano1, Kiyofumi Takabatake1, Masae Fujii1, Mei Hamada1, Ryo Tamamura4, Hitoshi Nagatsuka1

1. Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
2. Department of Life Science, Faculty of Science, Okayama University of Science, Okayama, Japan
3. Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
4. Department of Histology, Nihon University School of Dentistry at Matsudo, Japan

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Kawai H, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, Hamada M, Tamamura R, Nagatsuka H. Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. Int J Med Sci 2018; 15(12):1406-1414. doi:10.7150/ijms.24370. Available from

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Background: The tumor microenvironment and its stromal cells play an important role in cancer development and metastasis. Bone marrow-derived cells (BMDCs), a rich source of hematopoietic and mesenchymal stem cells, putatively contribute to this tumoral stroma. However their characteristics and roles within the tumor microenvironment are unclear. In the present study, BMDCs in the tumor microenvironment were traced using the green fluorescent protein (GFP) bone marrow transplantation model.

Methods: C57BL/6 mice were irradiated and rescued by bone marrow transplantation from GFP-transgenic mice. Lewis lung cancer cells were inoculated into the mice to generate subcutaneous allograft tumors or lung metastases. Confocal microscopy, immunohistochemistry for GFP, α-SMA, CD11b, CD31, CD34 and CD105, and double-fluorescent immunohistochemistry for GFP-CD11b, GFP-CD105 and GFP-CD31 were performed.

Results: Round and dendritic-shaped GFP-positive mononuclear cells constituted a significant stromal subpopulation in primary tumor peripheral area (PA) and metastatic tumor area (MA) microenvironment, thus implicating an invasive and metastatic role for these cells. CD11b co-expression in GFP-positive cells suggests that round/dendritic cell subpopulations are possibly BM-derived macrophages. Identification of GFP-positive mononuclear infiltrates co-expressing CD31 suggests that these cells might be BM-derived angioblasts, whereas their non-reactivity for CD34, CD105 and α-SMA implies an altered vascular phenotype distinct from endothelial cells. Significant upregulation of GFP-positive, CD31-positive and GFP/CD31 double-positive cell densities positively correlated with PA and MA (P<0.05).

Conclusion: Taken together, in vivo evidence of traceable GFP-positive BMDCs in primary and metastatic tumor microenvironment suggests that recruited BMDCs might partake in cancer invasion and metastasis, possess multilineage potency and promote angiogenesis.

Keywords: cancer microenvironment, bone marrow derived cells, lung cancer, animal model