Contributions of the host microenvironment to cancer-induced bone disease.

The bone marrow provides a specialized and highly supportive microenvironment for tumor growth and development of the associated bone disease. It is a preferred site for breast and prostate cancer bone metastasis and the hematologic malignancy, multiple myeloma. For many years, researchers have focused upon the interactions between tumor cells and the cells directly responsible for bone remodeling, namely osteoclasts and osteoblasts. However, there is ever-increasing evidence for a multitude of ways in which the bone marrow microenvironment can promote disease pathogenesis, including via cancer-associated fibroblasts, the hematopoietic stem cell niche, myeloid-derived suppressor cells, and the sympathetic nervous system. This review discusses the recent advances in our understanding of the contribution of the host microenvironment to the development of cancer-induced bone disease

Contributions of the host microenvironment to cancer-induced bone disease.

The bone marrow provides a specialized and highly supportive microenvironment for tumor growth and development of the associated bone disease. It is a preferred site for breast and prostate cancer bone metastasis and the hematologic malignancy, multiple myeloma. For many years, researchers have focused upon the interactions between tumor cells and the cells directly responsible for bone remodeling, namely osteoclasts and osteoblasts. However, there is ever-increasing evidence for a multitude of ways in which the bone marrow microenvironment can promote disease pathogenesis, including via cancer-associated fibroblasts, the hematopoietic stem cell niche, myeloid-derived suppressor cells, and the sympathetic nervous system. This review discusses the recent advances in our understanding of the contribution of the host microenvironment to the development of cancer-induced bone disease

IL-17/miR-192/IL-17Rs Regulatory Feedback Loop Facilitates Multiple Myeloma Progression

Multiple myeloma (MM) is a clonal plasma cell disorder which constitutes the second most common hematological malignancy, and remains an incurable tumor with poor survival. Recently, interleukin-17 (IL-17), produced locally in the tumor microenvironment, has been reported to play a crucial role in tumor immunity. In this study, we determined that exposure of MM cells to IL-17 had various promotive influences on different aspects of tumor progression. IL-17 significantly induced cell proliferation, inhibited cellular apoptosis, repressed cell adhesion to fibronectin and collagen I, and facilitated cell migration. Exposure to IL-17 also resulted in epithelial-mesenchymal transition (EMT), as evidenced by repression of the epithelial marker E-cadherin, and induction of the mesenchymal marker Vimentin, and EMT transcription factors Snail and Slug. Further experiments showed that IL-17 activated the oncogenic p65 transcription factor, which directly repressed the miR-192 gene via binding to the miR-192 promoter. Loss of miR-192 in MM cells can mimic the effects of IL-17, and was required for the above oncogenic effects of IL-17 on MM. Furthermore, we found that miR-192, and its homologous miR-215 directly targeted the 3'-untranslated regions of IL-17Rs, including IL-17RA and RE mRNA. By examining bone marrow specimens derived from MM patients, a negative correlation between miR-192 expression and IL-17 or IL-17RA expression was observed. Also, IL-17 was negatively correlated with E-cadherin and positively with Vimentin. Taken together, our study provides evidence that the IL-17/miR-192/IL-17Rs regulatory feedback loop is manifest in MM and might represent a promising and efficient prognostic marker and therapeutic target for MM