TGFB1 and neoplasm: Notably, these genes are all regulated by TGF-β via the canonical TGF-β/Smad pathway in metastatic cells.503,520,521 Either inhibition of TGF-β signaling with small-molecule inhibitors or inhibition of bone resorption with bisphosphonate is effective in decreasing TGF-β signaling activity in the bone metastases.522 This indicates that TGF-β released by osteoclastic bone resorption is the major source of TGF-β acting on tumor cells in bone.