Fig. 1.

Mechanisms regulating tumor dormancy in the bone. (a) Disseminated tumor cells (DTCs) home to the perivascular niche via bone microenvironmental factors such as CXCL12:CXCR4 and E-selectin. Within the perivascular niche, angiogenesis suppressors such as thrombospondin-1 (TSP1) promote tumor dormancy whereas proangiogenic factors including transforming growth factor beta 1 (TGFβ1) and periostin secreted from neovasculature induce tumor cell proliferation. DTCs prime mesenchymal stem cells to secrete exosomes containing miR-222/223 to maintain tumor cells in a dormant state. (b) DTCs residing in the endosteal niche co-opt the hematopoietic stem cell (HSC) niche to promote their survival and dormancy. Secretion of IL-1β and activation of mTOR signaling by CDH1:CDH2 interactions between osteoblasts and tumor cells stimulate tumor cell proliferation. (c) Tumor cell–intrinsic signaling pathways such as leukemia inhibitory factor receptor (LIFR), p38, and a hypoxia gene signature maintain tumor cells in a dormant state. CXCL12 = CXC chemokine ligand 12; CXCR4 = CXC motif chemokine receptor 4; CX3CL = CX3C motif chemokine ligand; CX3CR = CX3C motif chemokine receptor; TSP1 = thrombospondin-1; TGFβ1 = transforming growth factor beta 1; POSTN = periostin; HSC = hematopoietic stem cell; CDH1 = E-cadherin; CDH2 = N-cadherin; IL-1β = interleukin 1β; mTOR = mammalian target of rapamycin; LIFR = leukemia inhibitory factor receptor; STAT3 = signal transducer and activator of transcription 3; MSK1 = ribosomal protein S6 kinase A5; FBXW7 = F-box and WD repeat domain containing 7; IKKβ = inhibitor of nuclear factor kappa B kinase subunit beta; NR2F1 = nuclear receptor subfamily 2 group F member 1; p38 = mitogen activated protein kinase 14; ERK = extracellular-signal regulated kinase; BMP = bone morphogenetic protein; TGFβ2 = transforming growth factor beta 2