The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis
Abstract
:1. Introduction
2. Basics of Adipokines
3. Origin of Adipokines in the Process of Breast Cancer Bone Metastasis
4. Bone Marrow Adipocytes (BMAs)
5. The Role of Adipokines in Breast Cancer Bone Metastasis
6. Roles of BMAs in Bone Metastasis of Breast Cancer
6.1. Adipocytokines Secreted by BMA
6.2. Lipid Transfer from BMAs to Breast Cancer Cells
7. Therapeutic Targets of Adipokines and BMAs for Bone Metastasis of Breast Cancer
7.1. Adipokine Modulators
7.2. BMA Metabolism Inhibitors
7.3. BMA Inhibitors
8. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Adipokines | Roles in Breast Cancer |
---|---|
Leptin | promotes breast cancer cell proliferation by JAK-STAT, ERK1/2, AKT-GSK3 and PKC-α pathways [19,20] enhances breast cancer progression through the increase of cyclin D1, and CDK2 and by the decrease of p21, p27 and p53 [20,21,22] reduces breast cancer cell apoptosis by increasing survivin and bcl-2 and decreasing caspase-9 [21,23] enhances breast cancer cell migration and invasion through ACAT2 upregulation by PI3K/AKT/SREBP2 pathway [24] elevates angiogenesis by upregulating VEGF and Notch signaling [25,26] increased leptin in adipose stromal cells leads to the expression of EMT- and metastasis-related genes [27] |
Adiponectin | reduces breast cancer cell growth by inactivating p44/42 MAPK, activating AMPK pathway, and inhibiting AKT phosphorylation [28] induces breast cancer cell apoptosis through downregulating bcl-2 and upregulating p53, Bax and caspase 8 [29,30] induces autophagy related cell death by STK11/LKB1-AMPK-ULK1 pathway [31] Globular adiponectin promotes breast cancer cell invasion by autophagy [32] inhibits metastatic process by upregulation of LKB1 through AMPK-S6K axis activation [33] Globular adiponectin supports initial metastatic progression through autophagy activation [34] |
Autotaxin (ATX) | induces invasion and motility of breast cancer cells by gp130/JAK/STAT3 pathway [35] LPA, an ATX receptor, stimulates breast cancer cell migration by PI3K, PAK1 and MAPK pathways [36] Overexpression of ATX–LPA signaling promotes osteolytic bone metastasis of breast cancer cells [37] |
IL-6 | induces EMT of breast cancer cells by STAT3 pathway [38] associated with breast cancer stem cell self-renewal through the upregulation of Sox, c-Myc and Nanog [39] increases aromatase expression and stimulates estrogen synthesis, resulting in breast cancer progression [40] |
Resistin | enhances the metastatic potential of breast cancer by EMT and stemness [41] promotes breast cancer metastasis by phosphorylation of ezrin, radixin and moesin complex [42] High expression of resistin in breast cancer is associated with poor prognosis [43,44] |
IL-8 | IL-8 overexpression promotes cell migration via PI3K-AKT signaling pathway and EMT in triple-negative breast cancer [45] activates breast cancer-associated adipocytes (CAAs) and promotes tumorigenic effects of CAA [46] associated with early steps of breast cancer cell dissemination by adipocytes [47] activates osteoclastogenesis through CXCR1 receptor and promotes osteolytic bone metastasis in breast cancer [48] |
IL-11 | associated with stemness and metastasis in breast cancer [49] promotes osteoclastogenesis by sustaining the pool of osteoclast progenitor cells [50] involved in breast cancer bone metastasis through gp130/STAT3 pathway [51] activates osteoclastogenesis through JAK1/STAT3 pathway and promotes osteolytic bone metastasis [52] |
IGFBP2 | IGFBP2 overexpression is associated with breast cancer proliferation, invasion and migration [53] IGFBP2 overexpression is associated with breast cancer lymph node metastasis [54,55] induces metastatic bone colonization by endothelium recruitment through interaction with IGF type-I receptor [56] |
TGF-β | facilitates breast cancer migration and invasion through Smad3 and ERK/Sp1 signaling pathways [57] suppresses the antitumor function of ROR1-CAR T-cells against TNBC [58] promotes breast cancer progression by TWIST expression [59] induces bone metastasis by stimulating breast cancer cells to secrete PTHrP and IL-11 [60,61] stimulates breast cancer cells to secrete PTHrP to activate osteoclasts that increase bone resorption and promote tumor cell proliferation and survival [62] |
Oncostatin M (OSM) | OSM expression is correlated with breast cancer progression by JAK/STAT pathway [63] OSM expression is correlated with mesenchymal and stem cell-like differentiation in breast cancer by PI3K pathway [64] promotes metastasis in breast cancer through pre-vascular event and increased circulating tumor cells [65] High expression of OSM in breast cancer is associated with poor prognosis by estrogen receptor downregulation [66,67,68] activates osteoclastogenesis through AREG autocrine pathway to induce osteolytic bone metastasis [69] |
Osteopontin (OPN) | associated with tumor cell adhesion, migration and invasion in breast cancer by binding to integrins [70,71,72] OPN overexpression is associated with lymph node metastasis and poor prognosis in breast cancer [73] |
Pentraxin 3 (PTX3) | associated with stem-like features and EMT in breast cancer [74,75] increases cancer cell migration, macrophage migration to cancer cells and osteoclast formation, which result in osteolytic bone metastasis [76] |
IL-1B | drives breast cancer growth and bone metastasis [77] awakens breast cancer cells which are dormant within the bones to induce bone metastasis [78] an increased expression of IL-1β induces cancer cell colonization in bone marrow [79] |
MIF | promotes breast cancer cell proliferation by activation of PI3K/AKT signaling pathway [80] promotes tumor growth and metastasis by increasing recruitment of myeloid-derived suppressor cells [81] involved in pre-metastatic niche of bone metastasis process by intravasation, angiogenesis and EMT in breast cancer CTC [82] |
Cathepsin K | associated with breast cancer cell proliferation and metastasis [83] expressing fibroblasts promote invasion of breast cancer cells [84] induces osteolytic bone metastasis by activating osteoclasts [85,86] involved in breast cancer bone metastasis by splicing and activating SPARC [87] |
CCL2/MCP-1 | CCL2/CCR2 chemokine signaling promotes breast cancer growth and invasion [88] induces tamoxifen resistance by activating PI3K/AKT/mTOR in breast cancer [89] CCL2-induced chemokine cascade promotes breast cancer metastasis by increased recruitment of metastasis-associated macrophages [90] induces the invasiveness of human breast cancer cells through upregulation of ERO1-α and MMP-9 [91] CCL2/MCP-1 suppresses the expression of ICAM-1 and anchorage-independent tumor cell growth and cell migration, hence the suppression of bone metastasis [92] |
CXCL1 | promotes breast cancer migration, invasion, stem cells subpopulations, EMT, or mammosphere formation [93] |
VEGF | stimulates breast cancer metastasis in conjunction with cystathionine-γ-lyase [94] stimulates breast cancer cell migration by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network [95] confers cancer stemness by Wnt/β-catenin pathway in breast cancer cells [96] promotes breast cancer progression by EMT and activation of NF-κB and β-catenin [97] |
TNFα | induces trastuzumab resistance in HER2-positive breast cancer cell by MUC4 expression [98] promotes breast cancer metastasis by mesenchymal stromal cell activation via recruiting CXCR2-positive neutrophils [99] |
Parameters | BMA | Peripheral Tissue Adipocyte | ||
---|---|---|---|---|
cBMA | rBMA | White | Brown | |
Cell shape | Spherical | Spherical | Spherical | Elliptical |
Cell size | 37-41μm | 30-36μm | 25–200 μm | 15–60 μm |
Lipid droplets | Unilocular | Unilocular | Unilocular and large | Multilocular and small |
Location | Distal site | Proximal Central endosteal | Visceral Subcutaneous | Cervical Perirenal interscapular |
Function | No response to environmental stimuli | Response to environmental stimuli | Store energy in the form of TG | Fat consumption in order to maintain body temperature |
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Shin, E.; Koo, J.S. The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis. Int. J. Mol. Sci. 2020, 21, 4967. https://doi.org/10.3390/ijms21144967
Shin E, Koo JS. The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis. International Journal of Molecular Sciences. 2020; 21(14):4967. https://doi.org/10.3390/ijms21144967
Chicago/Turabian StyleShin, Eunah, and Ja Seung Koo. 2020. "The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis" International Journal of Molecular Sciences 21, no. 14: 4967. https://doi.org/10.3390/ijms21144967
APA StyleShin, E., & Koo, J. S. (2020). The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis. International Journal of Molecular Sciences, 21(14), 4967. https://doi.org/10.3390/ijms21144967