Tumor microenvironment as a target of osteolytic metastases

Bone is one of the most common sites of distant metastases from breast carcinoma. In lytic bone metastasis, tumor associated-osteoclasts are the main actors of bone resorption. Under physiological conditions, osteoclast formation is activated by cytokines and hormones produced by bone-resident cells, including osteoblasts and mesenchymal stem cells. However, when tumor cells spread to the bone, they disrupt the delicate balance between cells orchestrating osteoclast formation, thereby promoting bone resorption. Current treatments of metastatic bone disease are largely ineffective to improve patient survival, possibly due to their inability to interfere with the metabolic pathways that regulate the behavior and the cross-talk between cancer cells and osteoclasts. To add news insights into the complex pathogenesis of osteolytic metastases, we focused our investigations on the role of lactate in the metabolic symbiosis of bone metastasis. We found that human osteoclasts are characterized by an increased mitochondrial metabolism, that probably supports the biosynthetic needs for osteoclast formation and activation, and that a glycolytic switch support the resorption activity of osteoclasts. Moreover, osteoclasts are able to uptake lactate from the extracellular space, an energy-rich metabolite produced by the glycolytic metabolism of breast carcinoma cells. In osteoclasts, lactate fuels oxidative metabolism, thereby increasing tumor aggressiveness. However, the bone metastatic microenvironment is composed of several types of cells, including tumor-associated stromal cells, bone-resident cells, tumor cells, and cancer-initiating cells. Each cell type takes part to the complex process of metastatic lesions formation. In particular, cancer stem cells play a primary role in tumorigenesis. To gain a more in-depth knowledge on the interplay between cells of tumor bulk, we validated the most stable housekeeping genes for gene expression analysis on cancer stem cells. These findings lay the groundwork for future investigations on the cross-talk between stroma and tumor cells of the metastatic microenvironment.