Bone as a Preferential Site for Metastasis

Abstract

Bone marrow provides a unique microenvironment favoring the colonization and outgrowth of metastatic tumor cells. Despite the high incidence of bone metastasis in breast and prostate cancer patients, many of the molecular mechanisms controlling metastatic progression remain unclear. Several gene signatures associated with bone metastasis have been reported, but no metastasis-specific gene alterations have been identified. Therefore, there has been considerable interest in understanding how the bone microenvironment impacts the behavior of disseminated tumor cells (DTCs) prior to and following colonization of the bone. Substantial evidence indicates that disruption of normal bone homeostasis by tumor-derived factors establishes a premetastatic niche within the bone that favors DTC colonization. Following dissemination, bone resident cells and the surrounding stroma provide critical signals that support tumor cell colonization, survival, and eventual outgrowth. Clinical data suggest that patients can harbor DTCs for years to decades prior to developing overt bone metastases, suggesting a period of tumor dormancy occurs in the bone marrow. Several dormancy-promoting factors have been recently identified; however, critical questions surrounding the molecular triggers and timing of tumor cell emergence from dormancy remain. Here, we review how metastatic tumor cells co-opt the bone marrow microenvironment for metastatic progression and discuss emerging insights into how to more effectively target DTCs and prevent metastasis. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: BONE METASTASIS; COLONIZATION; DORMANCY; HOMING; PREMETASTATIC NICHE.

Figures

Figure 1

Metastatic progression in the bone. (A) Tumor‐derived factors promote the formation of a premetastatic niche in the bone prior to tumor cell dissemination. Factors such as lysyl oxidase (LOX) and C‐C motif chemokine ligand 2 (CCL2) disrupt normal bone homeostasis thereby favoring tumor cell colonization. (B) Disseminated tumor cells (DTCs) enter the circulation and can eventually home to the bone via microenvironmental signals including CXCL12:CXCR4 and E‐selectin. (C) Following extravasation, interaction with resident bone cells and signaling molecules such as leukemia inhibitory factor receptor (LIFR), p38, and thrombospondin‐1 (TSP1) maintain tumor cells in a dormant state. (D) Emergence of DTCs from dormancy results in the outgrowth into overt metastases. Tumor cell proliferation and osteolytic bone destruction is mediated by parathyroid hormone‐related protein (PTHrP), receptor activator of NFκB ligand (RANKL), and vascular cell adhesion molecule‐1 (VCAM‐1). The growth of neovasculature within the metastasis produces transforming growth factor beta 1 (TGFβ1) and periostin to further promote the proliferation of metastatic tumor cells. CAF = cancer‐associated fibroblast; CXCL12 = CXC Chemokine Ligand 12; LOX = lysyl oxidase; CCL2 = C‐C Motif Chemokine Ligand; IL‐6 = Interleukin‐6; DKK1 = Dickkopf WNT Signaling Pathway Inhibitor 1; CXCR4 = CXC Motif Chemokine Receptor 4; CX3CL = CX3C motif Chemokine Ligand; CX3CR = CX3C Motif Chemokine Receptor; TSP1 = Thrombospondin‐1; LIFR = Leukemia Inhibitory Factor Receptor; STAT3 = Signal transducer and activator of transcription 3; MSK1 = Ribosomal Protein S6 Kinase A5; NR2F1= Nuclear Receptor Subfamily 2 Group F Member 1; TAM receptors = TYRO3 Protein Tyrosine Kinase, AXL Receptor Tyrosine Kinase, MER Proto‐Oncogene Tyrosine Kinase; p38 = Mitogen Activated Protein Kinase 14; ERK = Extracellular‐signal Regulated Kinase; BMP = Bone Morphogenetic Protein; TGFb = Transforming Growth Factor Beta; GAS6 = Growth Arrest Specific 6; CDH1 = E‐cadherin; CDH2 = N‐cadherin; PTHrP = Parathyroid Hormone related Protein; PTHR1= Parathyroid Hormone Receptor 1; RANK = TNF Superfamily Member 11; VCAM1 = Vascular Cell Adhesion Molecule 1.