Abstract
Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) on osteoclastogenesis induced by triple negative BC cells. To this aim, we developed an in vitro human model of osteoclastogenesis from peripheral blood monocytes co-cultured with the triple negative SCP2 and the hormonal receptor positive MCF7 cell lines. Osteoclastogenesis was evaluated by TRAP staining, evaluation of F actin rings and Calcitonin Receptor expression. Eve significantly reduced differentiation induced by cancer cells and resulted more effective when evaluated in combination with Denosumab and Zoledronic Acid (Zol). Combination with Zol showed a total abrogation of osteoclast differentiation induced by the triple negative cell line, not by MCF7. Finally, we observed that Eve was active in the inhibition of the crosstalk between cancer cells and osteoclasts reproduced by our model, highlighting a new therapeutic choice for the subsetting of triple negative BC patients. We observed a difference in the response to bone-targeted therapy with respect to BC subtypes. Our model may represent a valid platform for preclinical trials on bone-targeted drugs and for the study of the interplay of BC with bone stromal cells.
Highlights
Bone is the most common site of breast cancer (BC) metastasis, with 70% of deceased BC patients carrying evidence of bone metastasis [1]
Conditioned media from SCP2 (CM) and RANKL-MCSF-supplemented media significantly induced osteoclastogenesis in
Hussein et al observed that Rapamycin, an analogous of Eve, significantly decreased the osteoclast population and osteolysis associated with experimental metastases in an in vivo model of bone metastasis developed by inoculating the murine triple negative BC cell line 4T1 [25]
Summary
Bone is the most common site of breast cancer (BC) metastasis, with 70% of deceased BC patients carrying evidence of bone metastasis [1]. The crosstalk between tumor and stromal cells is crucial for cancer progression both in primary tissue and secondary sites. Osteolytic bone metastasis from BC is the result of a pathological vicious cycle established by the reciprocal interactions between cancer cells (CCs), bone cells and bone microenvironment. Osteoclasts are the bone cells responsible for bone resorption in normal and pathologic conditions. The receptor activator of nuclear factor-κB ligand (RANK-L) binds and activates its receptor RANK on the surface of preosteoclasts stimulating their differentiation and maturation, leading to an increase in bone resorption. The unbalanced activation of osteoclasts results in a massive bone resorption, which, in turn, causes the release of the growth factors (GFs) stored in the bone matrix, promoting tumor growth with the establishment of a self-maintained vicious cycle [9]
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