Abstract
Metastasis requires numerous biological functions that jointly provide tumor cells from a primary site to seed and colonize a distant organ. Some of these activities are selected for in the primary site, whereas others are acquired at the metastatic niche. We provide molecular evidence showing that the BMP inhibitor, NOG, provides metastatic breast cancer cells with the ability to colonize the bone. NOG expression is acquired during the late events of metastasis, once cells have departed from the primary site, because it is not enriched in primary tumors with high risk of bone relapse. On the contrary, breast cancer bone metastatic lesions do select for high levels of NOG expression when compared with metastasis to the lung, liver, and brain. Pivotal to the bone colonization functions is the contribution of NOG to metastatic autonomous and nonautonomous cell functions. Using genetic approaches, we show that when NOG is expressed in human breast cancer cells, it facilitates bone colonization by fostering osteoclast differentiation and bone degradation and also contributes to metastatic lesions reinitiation. These findings reveal how aggressive cancer cell autonomous and nonautonomous functions can be mechanistically coupled to greater bone metastatic potential.
Highlights
NOG gene is required for accumulation of mature osteoclasts and proper skeletal development
Given that NOGGIN is a bone morphogenic protein (BMP) inhibitor, and BMP signaling defines the balance between differentiation of bone marrowderived cells to osteoclast or osteoblasts (8), we investigated the contribution of NOG in the formation of osteolytic/osteoblastic lesions
In comparison, prostate cancer renders osteoblastic lesions (8), whereas osteolytic lesions are largely associated with bone metastasis in breast cancer
Summary
NOG gene is required for accumulation of mature osteoclasts and proper skeletal development. Metastasis requires numerous biological functions that jointly provide tumor cells from a primary site to seed and colonize a distant organ Some of these activities are selected for in the primary site, whereas others are acquired at the metastatic niche. We show that when NOG is expressed in human breast cancer cells, it facilitates bone colonization by fostering osteoclast differentiation and bone degradation and contributes to metastatic lesions reinitiation. These findings reveal how aggressive cancer cell autonomous and nonautonomous functions can be mechanistically coupled to greater bone metastatic potential
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