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Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?

View Article: PubMed Central - PubMed

ABSTRACT

Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis.

No MeSH data available.


Related in: MedlinePlus

Molecular players of the metastasis formation cascade in the bone (A) and “bone vicious cycle” (B). (A) Metastasis-initiating cells (MICs) are a small fraction of long-term self-renewing tumor-initiating cells, characterized by specific driver mutations and high cellular plasticity [22]. Osteotropic events, like the 16q23 gain or macrophage-capping protein (CAPG)/ PDZ domain-containing protein GIPC1 (GIPC1) overexpression, will occur at early stages of tumor development [23,24]. Exosomes released from the primary tumor can facilitate the establishment of the pre-metastatic niche by transporting cytokines or being involved in gene transfer [22]. Upon the dormancy phase, vascular cell adhesion molecule 1 (VCAM-1) promotes osteolytic expansion of indolent bone micrometastases by engaging α4β1-positive osteoclast progenitors [25]; (B) the “vicious-cycle of bone metastases” results from the complex interaction between tumor cells, bone forming osteoblasts, bone resorbing osteoclasts, and a variety of cells from the bone microenvironment and immune system, like cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), dendritic cells (DCs), T cells and macrophages [26]. Osteoblasts are activated by tumor-derived parathyroid hormone-related protein (PTHrP), leading to increased production of receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL binds to receptor activator of nuclear factor kappa-B (RANK) expressed on hematopoietic osteoclast precursors, leading to osteoclastogenesis and bone resorption. Bone matrix-stored minerals and growth factors are released and activated, further feeding the tumor cell growth. In osteoblastic bone metastases, like in prostate cancer, osteoblasts activity is stimulated by several growth factors like basic fibroblast growth factor (bFGF), bone morphogenetic proteins (BMPs), endothelin 1 (ET-1), transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF-1), and deposition of disorganized new bone matrix is exacerbated [27]. miRNAs can act as master regulators of gene expression, having a positive (+) or negative (−) effect on specific genes that will control multiple aspects of bone metastasis formation [28]. BMI1, polycomb complex protein; CCL-2, Ccl2 chemokine (C–C motif) ligand 2; CD44, cell Surface Glycoprotein CD44; CTSK, cathepsin K; CSF-1, colony stimulating factor 1; CXCL12, C–X–C motif chemokine 12; CXCR4, C–X–C chemokine receptor type 4; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; ENT, equilibrative nucleoside transporter 1; ETR, endothelin receptor; FIH-1, factor Inhibiting HIF1; HEF-1, human enhancer of filamentation 1; IGFR, insulin-like growth factor 1 (IGF-1) receptor; IL, interleukin; KLF4, kruppel-like factor 4; ITGA5, integrin Subunit Alpha 5; MAF, V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog; MET, hepatocyte growth factor receptor; MMP, matrix metalloproteinases; mTORC1, mammalian target of rapamycin complex 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH1R, parathyroid hormone 1 receptor; RDx, radixin; SOX4, transcription factor SOX-4; TCF, transcription factor family; TGIF2, TGF beta induced factor homeobox 2; TGFR, transforming growth factor beta receptor II; uPAR, urokinase receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WNT, wingless-related integration site proteins; ZEB, zinc finger E-box-binding homeobox 1.
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ijms-17-01415-f001: Molecular players of the metastasis formation cascade in the bone (A) and “bone vicious cycle” (B). (A) Metastasis-initiating cells (MICs) are a small fraction of long-term self-renewing tumor-initiating cells, characterized by specific driver mutations and high cellular plasticity [22]. Osteotropic events, like the 16q23 gain or macrophage-capping protein (CAPG)/ PDZ domain-containing protein GIPC1 (GIPC1) overexpression, will occur at early stages of tumor development [23,24]. Exosomes released from the primary tumor can facilitate the establishment of the pre-metastatic niche by transporting cytokines or being involved in gene transfer [22]. Upon the dormancy phase, vascular cell adhesion molecule 1 (VCAM-1) promotes osteolytic expansion of indolent bone micrometastases by engaging α4β1-positive osteoclast progenitors [25]; (B) the “vicious-cycle of bone metastases” results from the complex interaction between tumor cells, bone forming osteoblasts, bone resorbing osteoclasts, and a variety of cells from the bone microenvironment and immune system, like cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), dendritic cells (DCs), T cells and macrophages [26]. Osteoblasts are activated by tumor-derived parathyroid hormone-related protein (PTHrP), leading to increased production of receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL binds to receptor activator of nuclear factor kappa-B (RANK) expressed on hematopoietic osteoclast precursors, leading to osteoclastogenesis and bone resorption. Bone matrix-stored minerals and growth factors are released and activated, further feeding the tumor cell growth. In osteoblastic bone metastases, like in prostate cancer, osteoblasts activity is stimulated by several growth factors like basic fibroblast growth factor (bFGF), bone morphogenetic proteins (BMPs), endothelin 1 (ET-1), transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF-1), and deposition of disorganized new bone matrix is exacerbated [27]. miRNAs can act as master regulators of gene expression, having a positive (+) or negative (−) effect on specific genes that will control multiple aspects of bone metastasis formation [28]. BMI1, polycomb complex protein; CCL-2, Ccl2 chemokine (C–C motif) ligand 2; CD44, cell Surface Glycoprotein CD44; CTSK, cathepsin K; CSF-1, colony stimulating factor 1; CXCL12, C–X–C motif chemokine 12; CXCR4, C–X–C chemokine receptor type 4; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; ENT, equilibrative nucleoside transporter 1; ETR, endothelin receptor; FIH-1, factor Inhibiting HIF1; HEF-1, human enhancer of filamentation 1; IGFR, insulin-like growth factor 1 (IGF-1) receptor; IL, interleukin; KLF4, kruppel-like factor 4; ITGA5, integrin Subunit Alpha 5; MAF, V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog; MET, hepatocyte growth factor receptor; MMP, matrix metalloproteinases; mTORC1, mammalian target of rapamycin complex 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH1R, parathyroid hormone 1 receptor; RDx, radixin; SOX4, transcription factor SOX-4; TCF, transcription factor family; TGIF2, TGF beta induced factor homeobox 2; TGFR, transforming growth factor beta receptor II; uPAR, urokinase receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WNT, wingless-related integration site proteins; ZEB, zinc finger E-box-binding homeobox 1.

Mentions: Since the initial steps of metastasis formation may occur early during tumor development and therefore escape detection (Figure 1A), the therapeutic focus has been on the colonization step, which constitutes the critical transition between micrometastases and macrometastasis [15]. The “vicious cycle of bone metastases” has been deeply dissected, and our knowledge on the molecular players and mechanisms has evolved substantially (Figure 1B) [16,17,18].


Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?
Molecular players of the metastasis formation cascade in the bone (A) and “bone vicious cycle” (B). (A) Metastasis-initiating cells (MICs) are a small fraction of long-term self-renewing tumor-initiating cells, characterized by specific driver mutations and high cellular plasticity [22]. Osteotropic events, like the 16q23 gain or macrophage-capping protein (CAPG)/ PDZ domain-containing protein GIPC1 (GIPC1) overexpression, will occur at early stages of tumor development [23,24]. Exosomes released from the primary tumor can facilitate the establishment of the pre-metastatic niche by transporting cytokines or being involved in gene transfer [22]. Upon the dormancy phase, vascular cell adhesion molecule 1 (VCAM-1) promotes osteolytic expansion of indolent bone micrometastases by engaging α4β1-positive osteoclast progenitors [25]; (B) the “vicious-cycle of bone metastases” results from the complex interaction between tumor cells, bone forming osteoblasts, bone resorbing osteoclasts, and a variety of cells from the bone microenvironment and immune system, like cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), dendritic cells (DCs), T cells and macrophages [26]. Osteoblasts are activated by tumor-derived parathyroid hormone-related protein (PTHrP), leading to increased production of receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL binds to receptor activator of nuclear factor kappa-B (RANK) expressed on hematopoietic osteoclast precursors, leading to osteoclastogenesis and bone resorption. Bone matrix-stored minerals and growth factors are released and activated, further feeding the tumor cell growth. In osteoblastic bone metastases, like in prostate cancer, osteoblasts activity is stimulated by several growth factors like basic fibroblast growth factor (bFGF), bone morphogenetic proteins (BMPs), endothelin 1 (ET-1), transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF-1), and deposition of disorganized new bone matrix is exacerbated [27]. miRNAs can act as master regulators of gene expression, having a positive (+) or negative (−) effect on specific genes that will control multiple aspects of bone metastasis formation [28]. BMI1, polycomb complex protein; CCL-2, Ccl2 chemokine (C–C motif) ligand 2; CD44, cell Surface Glycoprotein CD44; CTSK, cathepsin K; CSF-1, colony stimulating factor 1; CXCL12, C–X–C motif chemokine 12; CXCR4, C–X–C chemokine receptor type 4; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; ENT, equilibrative nucleoside transporter 1; ETR, endothelin receptor; FIH-1, factor Inhibiting HIF1; HEF-1, human enhancer of filamentation 1; IGFR, insulin-like growth factor 1 (IGF-1) receptor; IL, interleukin; KLF4, kruppel-like factor 4; ITGA5, integrin Subunit Alpha 5; MAF, V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog; MET, hepatocyte growth factor receptor; MMP, matrix metalloproteinases; mTORC1, mammalian target of rapamycin complex 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH1R, parathyroid hormone 1 receptor; RDx, radixin; SOX4, transcription factor SOX-4; TCF, transcription factor family; TGIF2, TGF beta induced factor homeobox 2; TGFR, transforming growth factor beta receptor II; uPAR, urokinase receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WNT, wingless-related integration site proteins; ZEB, zinc finger E-box-binding homeobox 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037694&req=5

ijms-17-01415-f001: Molecular players of the metastasis formation cascade in the bone (A) and “bone vicious cycle” (B). (A) Metastasis-initiating cells (MICs) are a small fraction of long-term self-renewing tumor-initiating cells, characterized by specific driver mutations and high cellular plasticity [22]. Osteotropic events, like the 16q23 gain or macrophage-capping protein (CAPG)/ PDZ domain-containing protein GIPC1 (GIPC1) overexpression, will occur at early stages of tumor development [23,24]. Exosomes released from the primary tumor can facilitate the establishment of the pre-metastatic niche by transporting cytokines or being involved in gene transfer [22]. Upon the dormancy phase, vascular cell adhesion molecule 1 (VCAM-1) promotes osteolytic expansion of indolent bone micrometastases by engaging α4β1-positive osteoclast progenitors [25]; (B) the “vicious-cycle of bone metastases” results from the complex interaction between tumor cells, bone forming osteoblasts, bone resorbing osteoclasts, and a variety of cells from the bone microenvironment and immune system, like cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), dendritic cells (DCs), T cells and macrophages [26]. Osteoblasts are activated by tumor-derived parathyroid hormone-related protein (PTHrP), leading to increased production of receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL binds to receptor activator of nuclear factor kappa-B (RANK) expressed on hematopoietic osteoclast precursors, leading to osteoclastogenesis and bone resorption. Bone matrix-stored minerals and growth factors are released and activated, further feeding the tumor cell growth. In osteoblastic bone metastases, like in prostate cancer, osteoblasts activity is stimulated by several growth factors like basic fibroblast growth factor (bFGF), bone morphogenetic proteins (BMPs), endothelin 1 (ET-1), transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF-1), and deposition of disorganized new bone matrix is exacerbated [27]. miRNAs can act as master regulators of gene expression, having a positive (+) or negative (−) effect on specific genes that will control multiple aspects of bone metastasis formation [28]. BMI1, polycomb complex protein; CCL-2, Ccl2 chemokine (C–C motif) ligand 2; CD44, cell Surface Glycoprotein CD44; CTSK, cathepsin K; CSF-1, colony stimulating factor 1; CXCL12, C–X–C motif chemokine 12; CXCR4, C–X–C chemokine receptor type 4; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; ENT, equilibrative nucleoside transporter 1; ETR, endothelin receptor; FIH-1, factor Inhibiting HIF1; HEF-1, human enhancer of filamentation 1; IGFR, insulin-like growth factor 1 (IGF-1) receptor; IL, interleukin; KLF4, kruppel-like factor 4; ITGA5, integrin Subunit Alpha 5; MAF, V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog; MET, hepatocyte growth factor receptor; MMP, matrix metalloproteinases; mTORC1, mammalian target of rapamycin complex 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH1R, parathyroid hormone 1 receptor; RDx, radixin; SOX4, transcription factor SOX-4; TCF, transcription factor family; TGIF2, TGF beta induced factor homeobox 2; TGFR, transforming growth factor beta receptor II; uPAR, urokinase receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WNT, wingless-related integration site proteins; ZEB, zinc finger E-box-binding homeobox 1.
Mentions: Since the initial steps of metastasis formation may occur early during tumor development and therefore escape detection (Figure 1A), the therapeutic focus has been on the colonization step, which constitutes the critical transition between micrometastases and macrometastasis [15]. The “vicious cycle of bone metastases” has been deeply dissected, and our knowledge on the molecular players and mechanisms has evolved substantially (Figure 1B) [16,17,18].

View Article: PubMed Central - PubMed

ABSTRACT

Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis.

No MeSH data available.


Related in: MedlinePlus