RSPO2/RANKL-LGR4 signaling regulates osteoclastic pre-metastatic niche formation and bone metastasis

Abstract Background To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. Methods The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. Results LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. Conclusion LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC.

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Roundabout receptors: new actors in bone metastatic niche formation

Bone Abstracts ◽

10.1530/boneabs.5.cabs.op1.2 ◽

2016 ◽

Author(s):

Lise Clement-Demange ◽

Pape Francois Le ◽

Benedicte Eckel ◽

Sandra Geraci ◽

Chantal Diaz-Latoud ◽

...

Keyword(s):

Metastatic Niche ◽

Niche Formation ◽

Roundabout Receptors

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Faculty Opinions recommendation of Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725503521.793507919 ◽

2015 ◽

Author(s):

Sebastian Stintzing

Keyword(s):

Pancreatic Cancer ◽

Metastatic Niche ◽

Niche Formation

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The dynamic behavior of lipid droplets in the pre-metastatic niche

Cell Death and Disease ◽

10.1038/s41419-020-03207-0 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Chunliang Shang ◽

Jie Qiao ◽

Hongyan Guo

Keyword(s):

Tumor Cells ◽

Immune Cells ◽

Stromal Cells ◽

Lipid Droplets ◽

Metastatic Tumor ◽

Current Evidence ◽

Biological Functions ◽

Metastatic Niche ◽

Niche Formation

AbstractThe pre-metastatic niche is a favorable microenvironment for the colonization of metastatic tumor cells in specific distant organs. Lipid droplets (LDs, also known as lipid bodies or adiposomes) have increasingly been recognized as lipid-rich, functionally dynamic organelles within tumor cells, immune cells, and other stromal cells that are linked to diverse biological functions and human diseases. Moreover, in recent years, several studies have described the indispensable role of LDs in the development of pre-metastatic niches. This review discusses current evidence related to the biogenesis, composition, and functions of LDs related to the following characteristics of the pre-metastatic niche: immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, reprogramming. We also address the function of LDs in mediating pre-metastatic niche formation. The potential of LDs as markers and targets for novel antimetastatic therapies will be discussed.

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Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis

Journal of Molecular Medicine ◽

10.1007/s00109-011-0855-y ◽

2012 ◽

Vol 90 (7) ◽

pp. 803-815 ◽

Cited By ~ 129

Author(s):

Carmen Chak-Lui Wong ◽

Huafeng Zhang ◽

Daniele M. Gilkes ◽

Jasper Chen ◽

Hong Wei ◽

...

Keyword(s):

Breast Cancer ◽

Lung Metastasis ◽

Hypoxia Inducible Factor ◽

Metastatic Niche ◽

Hypoxia Inducible Factor 1 ◽

Niche Formation

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Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

10.1101/2020.02.11.943860 ◽

2020 ◽

Author(s):

Bethany A. Kerr ◽

Koran S. Harris ◽

Lihong Shi ◽

Jeffrey S. Willey ◽

David R. Soto-Pantoja ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Bone Formation ◽

Tumor Growth ◽

Tumor Size ◽

Metastatic Niche ◽

Primary Tumors ◽

Niche Formation ◽

Cell Mobilization ◽

Tgf Β1

ABSTRACTThe development of distant metastasis is the main cause of prostate cancer (CaP)-related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-β1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-β1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-β1. Similar to TSP-1 deletion, loss of platelet TGF-β1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release. Within the bone microenvironment, platelet TGF-β1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-β1 axis regulates pre-metastatic niche formation and tumor-induced bone turnover. Targeting the platelet release of TSP-1 or TGF-β1 represents a potential method to interfere with the process of CaP metastasis to bone.

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Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

10.1101/2020.09.11.293837 ◽

2020 ◽

Author(s):

Suzann Duan ◽

Senny Nordmeier ◽

Aidan E. Byrnes ◽

Iain L. O. Buxton

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Endothelial Cell ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Purinergic Signaling ◽

Endothelial Cell Migration ◽

Metastatic Niche ◽

Niche Formation

AbstractMetastasis accounts for over 90% of cancer-related deaths. The mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV induced-proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth.

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Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Cancers ◽

10.3390/cancers11060874 ◽

2019 ◽

Vol 11 (6) ◽

pp. 874 ◽

Cited By ~ 15

Author(s):

Jiangang Zhao ◽

Hans A. Schlößer ◽

Zhefang Wang ◽

Jie Qin ◽

Jiahui Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nk Cells ◽

Extracellular Vesicles ◽

Nk Cell ◽

Killer Cell ◽

Pancreatic Cancer Cell Line ◽

Ductal Adenocarcinoma ◽

Metastatic Niche ◽

Niche Formation ◽

Tgf Β1

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.

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