Generation of induced tumor-suppressing cells from osteoblasts and mesenchymal stem cells

Abstract Background The current treatment for breast cancer-associated bone metastasis is palliative, and there is an unmet need to develop an effective regimen. In this study, we examined the possibility of conditioned medium (CM)-based therapy with bone-forming osteoblasts and their precursors, mesenchymal stem cells (MSCs). Methods Tumor cell lines, human breast cancer tissues, and a mouse model of mammary tumors and bone metastasis were employed to examine the tumor-suppressing effect of osteoblast- and MSC-derived CM. Tumor-driven osteolysis was evaluated using micro CT imaging and histology, and tumorigenic signaling was analyzed with an antibody-based protein array and Western blotting in response to the overexpression and RNA silencing of the key regulatory factors. Results Osteoblast- and MSC-derived CM without any overexpression did not alter the progression of mammary tumor cells. However, overexpressing Lrp5 and Snail converted them into induced tumor-suppressing (iTS) cells. In the mouse model, the systemic administration of iTS cell-derived CM reduced the weight of mammary tumors and suppressed tumor-induced osteolysis. The same outcome was observed with the overexpression of p53, a tumor-suppressing gene. In Lrp5-overexpressing CM, cytokines such as CXCL2 and LIF were downregulated, while p53 and Trail, an apoptosis-inducing factor, were upregulated. The overexpression of p53 in MSCs also reduced CXCL2 and LIF with an elevation of Trail. Notably, iTS cells were generated from mammary tumor cells by the overexpression of Lrp5 or Snail. We postulate that natural selection via cell competitions might be involved in the anti-tumor capability of iTS cells against tumor cells. Conclusions This study demonstrates that osteoblasts and MSCs can be converted into iTS cells by overexpressing the selected genes, and p53 is involved in the action of iTS cells. An iTS CM-based therapy may provide a novel option to treat primary and metastatic breast cancers.