Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer

Abstract

Cysteine cathepsin proteases contribute to many normal cellular functions, and their aberrant activity within various cell types can contribute to many diseases, including breast cancer. It is now well accepted that cathepsin proteases have numerous cell-specific functions within the tumor microenvironment that function to promote tumor growth and invasion, such that they may be valid targets for anti-metastatic therapeutic approaches. Using activity-based probes, we have examined the activity and expression of cysteine cathepsins in a mouse model of breast cancer metastasis to bone. In mice bearing highly metastatic tumors, we detected abundant cysteine cathepsin expression and activity in myeloid-derived suppressor cells (MDSCs). These immature immune cells have known metastasis-promoting roles, including immunosuppression and osteoclastogenesis, and we assessed the contribution of cysteine cathepsins to these functions. Blocking cysteine cathepsin activity with multiple small-molecule inhibitors resulted in enhanced differentiation of multinucleated osteoclasts. This highlights a potential role for cysteine cathepsin activity in suppressing the fusion of osteoclast precursor cells. In support of this hypothesis, we found that expression and activity of key cysteine cathepsins were downregulated during MDSC-osteoclast differentiation. Another cysteine protease, legumain, also inhibits osteoclastogenesis, in part through modulation of cathepsin L activity. Together, these data suggest that cysteine protease inhibition is associated with enhanced osteoclastogenesis, a process that has been implicated in bone metastasis.

Myoepithelial cell‐specific expression of stefin A as a suppressor of early breast cancer invasion

“…The protocol followed was as previously described . Specifically, for cathepsin B activity gels, activity‐based probes [GB123 (1 μ m ) [28] or BMV109 (0.1 μ m ) ] were added to lysates from a 100× stock, and proteins were incubated for 30 min at 37 °C.…”

Location of tumor affects local and distant immune cell type and number

“…The canonical model describing this process entails secretion of tumor-derived factors, especially receptor activator of nuclear factor kappa-B ligand), which stimulates activation of osteoclast precursors to mature osteoclast, which then resorb bone, leading to the release of protumorigenic growth factors and formation of a niche conducive of tumor growth [19][20][21]. Previously, we and others have shown that myeloid-derived suppressor cells (MDSC) function as a direct source of osteoclasts [22][23][24]. An important finding in our studies was only MDSC within the bone TME differentiated into osteoclast, whereas MDSC from nonbone sites of BCa metastasis or from spleen did not [22].…”

The Role of Cathepsins in the Growth of Primary and Secondary Neoplasia in the Bone

“…Several reports have demonstrated that the inhibition of cathepsin by agents such as CA074 (CatB inhbitor) and JMP-OEt (pan cathepsin inhibitor) leads to an increase in osteoclastogenesis, osteoclast surface area, and average cell size [95,96]. This suggests that cathepsin inhibition may increase the proliferation rates of precursor cells, thereby increasing the number of fusion events or the rate of osteoclast fusion.…”