OPN is an integrin-binding glycoprotein also known as secreted phosphoprotein 1 (SPP1). OPN is so named because it was first discovered in osteoblasts and osteoclasts. The latter is developed from the macrophage lineage. OPN protein has a secreted form and an intracellular form. The secreted OPN has two integrin-binding domains which can adhere to integrins on the surfaces of macrophages, making it a potent chemoattractant as well as an activator of macrophages. In innate immunological cells such as dendritic cells, OPN can be activated upon infection. The OPN-integrin binding can trigger downstream macrophage activities including TNF secretion, producing an inflammatory microenvironment. Poor prognosis of HCC was correlated with elevated OPN RNA, tissue OPN protein levels and pre-operative serum OPN protein levels. An anti-OPN antibody has been shown to defer the growth and metastasis of breast cancer in a mice model. As macrophages can also secret OPN, PTM and OPN form a vicious autocrine/paracrine cycle for the progression of cancer. Thus, in the future, novel strategies to break this cycle could bring to new anti-HCC treatments.