PLD1/2 present in EVs from prostate cancer cells activates osteoblast differentiation through enhancing extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, tissue-nonspecific alkaline phosphatase activity and expression of osteogenic differentiation markers such as Alpl, Osx, Opn, Ocn and Dmp1, thus establishing a tumor-favoring microenvironment before bone metastasis (68). The gene discussed is SPP1; the disease is neoplasm.