Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature
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Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis.
A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow.
Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels.
This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.
KeywordsBone marrow transplantation Endothelial cells Melanoma stroma Angiogenesis Cell migration
We thank Angelo A. Cardoso, Indiana University School of Medicine, Indianapolis-IN, USA, for the collaboration in scientific discussions; Camila Cristina Branquinho de Oliveira Menezes and Patrícia Vianna Bonini Palma, Hemocentro-FMRP-USP, Ribeirão Preto, Brazil, for support with the flow cytometry; and Sandra Navarro Bresciani, Hemocentro-FMRP-USP, Ribeirão Preto, Brazil, for support with figure design. We also thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the financial support for this study.
Compliance with ethical standards
All the animal procedures of this study were done in agreement with the ETHICAL PRINCIPLES IN ANIMAL RESEARCH adopted by the Brazilian College of Animal Experimentation (COBEA) and this study, under protocol number 043/2010, was approved by the Medical School of Ribeirão Preto of the University of São Paulo—Ethical Commission of Ethics in Animal Research (CETEA).
Conflict of interest
The authors declare that they have no conflict of interest.
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