T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer.
Bone metastases, present in 70% of patients with metastatic breast cancer, lead to skeletal disease, fractures and intense pain, which are all believed to be mediated by tumor cells. Engraftment of tumor cells is supposed to be preceded by changes in the target tissue to create a permissive microenvironment, the pre-metastatic niche, for the establishment of the metastatic foci. In bone metastatic niche, metastatic cells stimulate bone consumption resulting in the release of growth factors that feed the tumor, establishing a vicious cycle between the bone remodeling system and the tumor itself. Yet, how the pre-metastatic niches arise in the bone tissue remains unclear. Here we show that tumor-specific T cells induce osteolytic bone disease before bone colonization. T cells pro-metastatic activity correlate with a pro-osteoclastogenic cytokine profile, including RANKL, a master regulator of osteoclastogenesis. In vivo inhibition of RANKL from tumor-specific T cells completely blocks bone loss and metastasis. Our results unveil an unexpected role for RANKL-derived from T cells in setting the pre-metastatic niche and promoting tumor spread. We believe this information can bring new possibilities for the development of prognostic and therapeutic tools based on modulation of T cell activity for prevention and treatment of bone metastasis.
Experimental Medicine Program, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
Ana Carolina
AC
Monteiro
Ana Carolina
AC
Leal
Triciana
T
Gonçalves-Silva
Ana Carolina T
AC
Mercadante
Fabiola
F
Kestelman
Sacha Braun
SB
Chaves
Ricardo Bentes
RB
Azevedo
João P
JP
Monteiro
Adriana
A
Bonomo
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D001859:Bone Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary*; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D051379:Mice; D008954:Models, Biological; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism; D010014:Osteolysis / Q000276:immunology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D000951:Antigens, Neoplasm; D016207:Cytokines; D053245:RANK Ligand