The anti-metastatic micro-environment of the bone: Importance of osteocyte Cx43 hemichannels

• Connexin 43 (Cx43) is an endogenous bone anti-metastatic factor for breast cancer cells present in osteocytes.
• Osteocyte Cx43 proteins function as mechanosensitive hemichannels that release anti-metastatic molecules like ATP.
• Bisphosphonate drugs, adjuvants applied in anti-breast cancer treatments, lead to osteocyte Cx43-hemichannel opening.
• Activation of osteocyte Cx43 hemichannels by mechanical stimulation or bisphosphonate drugs suppresses bone metastases.
• Osteocyte Cx43 hemichannels are metastatic supppressors critical for the therapeutic response towards anti-metastasis drugs.

Bone metastases of tumor cells are a common and life-threatening feature of a variety of late-stage cancers, including breast cancers. However, until now, much less has been known about the intrinsic anti-metastatic properties of the bones and how these could be exploited to prevent or treat bone metastases. Very recently, native Cx43 hemichannels present in osteocytes have been identified as important anti-metastatic signaling complexes by establishing high local extracellular ATP levels. Moreover, bisphosphonate drugs, applied as adjuvant therapies in the treatment of breast cancer patients and bone diseases, are known to display anti-metastatic properties. Now, it became clear that these compounds exert their effects through osteocyte Cx43 hemichannels, thereby triggering their opening and promoting ATP release in the extracellular micro-environment. Hence, endogenous osteocyte Cx43 hemichannels emerge as important and promising therapeutic targets for the prevention of bone metastases and/or clinical treatment of bone-metastasized breast cancers.