SPP1 and cancer: Relatively high expression of genes responsible for osteopontin and/or osteonectin synthesis and for their receptors has already been observed in fibroblasts, the extracellular matrix surrounding (metastatic) cancer cells, and in macrophages.53,57 Upon cancer development/progression, systemic expression/synthesis of these molecules may not directly depend on the metabolic status anymore, but rather be influenced by malignant cells and their metabolic activity, which generally is much more rapid than that of healthy cells.