Figure 2.

Schematic illustration of anti-tumor microenvironment in the bone. At the left side of the panel are the osteocytes and the right side are the breast cancer cells. These cells interact in a healthy bone environment. The numbers indicate the steps of events that may happen during breast metastasis described in the review. ① The interaction of metastatic cells with osteoblast promotes dormancy. ② Physiological level of mechanical loading stimulates osteocyte release of anabolic factors, Wnt, and OPN, to increase osteoblast differentiation, activity, and bone strength. ③ High concentration of OPN reduces EMT in metastatic cells. ④ Mechanical loading increases opening of Cx43 hemichannels and the release of ATP. ⑤ eATP inhibits osteoclast activity and ⑥ also inhibits Treg formation and stimulates immune surveillance. ⑦ eATP activates P2X receptor and reduces the proliferation, migration, and metastatic potential of cancer cells.