Role of Altered Metabolic Microenvironment in Osteolytic Metastasis

Metastatic bone disease is generally incurable and leads to pathological fractures, pain, hypercalcemia, spinal cord compression and decreased mobility. The skeleton is the major site of bone metastases from solid cancers, including breast and prostate carcinoma. Bone metastasis is facilitated by activation of bone-resorbing osteoclasts, terminally differentiated multinucleated cells formed by fusion from monocytic precursors. Cancer cells are known to produce specific factors that stimulate osteoclast differentiation and function. Of interest, cancer cells are also known to alter their own bioenergetics increasing the use of glycolysis for their survival and function. Such change in energy utilization by cancer cells would result in altered levels of cell-permeable metabolites, including glucose, lactate, and pyruvate. Osteoclast resorption is energy-expensive, and we have previously demonstrated that during differentiation osteoclasts actively adapt to their bioenergetics microenvironment. We hypothesize that altered bioenergetics state of cancer cells will also modify the bioenergetics substrate availability for the tissue-resident bone cells, potentially creating a favorable milieu for pathological osteolysis. The goals of this review are to analyze how metastasizing cancer cells change the availability of energy substrates in bone microenvironment; and to assess how the altered bioenergetics may affect osteoclast differentiation and activity.