Figure 2.

PTHrP dictates disseminated tumor cell fate in the bone to drive metastasis formation. Upon dissemination to the bone, surviving tumor cells can proliferate into a micrometastasis. Tumor cell secretion of PTHrP signals through the PTH1 receptor (PTH1R) on osteoblast lineage cells to stimulate RANKL production and osteoclastogenesis. Osteoclast-mediated resorption releases pro-tumorigenic factors from the bone matrix such as TGF-β, matrix metalloproteinases and other growth factors that further fuel tumor cell colonization, proliferation, and PTHrP production. Alternatively, disseminated tumor cells instead enter a prolonged dormant state. PTHrP drives tumor cell escape from dormancy and metastatic outgrowth via multiple mechanisms: (1) increased proliferation, (2) apoptosis resistance, (3) increased angiogenesis, (4) decreased immunosurveillance and myeloid-derived suppressor cell recruitment, (5) decreased expression of known quiescence factors (e.g., LIFR). PTHrP, parathyroid hormone-related protein; PTH1R, parathyroid hormone-related protein type 1 receptor; RANKL, receptor activator of nuclear factor–kappa B (NF_κB) ligand; LIFR, leukemia inhibitory factor receptor (LIFR); TSP-1, thrombospondin-1.