scholarly journals Pre-metastatic Niche Formation in Different Organs Induced by Tumor Extracellular Vesicles

2021 ◽  
Vol 9 ◽  
Author(s):  
Qi Dong ◽  
Xue Liu ◽  
Ke Cheng ◽  
Jiahao Sheng ◽  
Jing Kong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Extracellular Vesicles ◽  
Critical Role ◽  
Matrix Remodeling ◽  
Metastatic Niche ◽  
Primary Tumors ◽  
Target Organs ◽  
Bone Marrow Derived Cells ◽  
Metastatic Microenvironment ◽  
Underlying Mechanisms

Primary tumors selectively modify the microenvironment of distant organs such as the lung, liver, brain, bone marrow, and lymph nodes to facilitate metastasis. This supportive metastatic microenvironment in distant organs was termed the pre-metastatic niche (PMN) that is characterized by increased vascular permeability, extracellular matrix remodeling, bone marrow-derived cells recruitment, angiogenesis, and immunosuppression. Extracellular vesicles (EVs) are a group of cell-derived membranous structures that carry various functional molecules. EVs play a critical role in PMN formation by delivering their cargos to recipient cells in target organs. We provide an overview of the characteristics of the PMN in different organs promoted by cancer EVs and the underlying mechanisms in this review.

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

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.

scholarly journals Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3752
Author(s):  
Ru Li ◽  
Annie Wen ◽  
Jun Lin
Keyword(s):  
Bone Marrow ◽  
Tumor Cells ◽  
Inflammatory Cytokines ◽  
Primary Tumor ◽  
Metastatic Progression ◽  
Colony Stimulating Factor ◽  
Metastatic Niche ◽  
Bone Marrow Derived Cells ◽  
Stimulating Factor ◽  
Pro Inflammatory Cytokines

In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C–X–C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ’s microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future.

scholarly journals Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis

2017 ◽  
Vol 114 (11) ◽  
pp. 2964-2969 ◽  
Author(s):  
Yiwen Zhang ◽  
Jian Zhang ◽  
Rong Yan ◽  
Jingluan Tian ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Critical Role ◽  
In Vivo Model ◽  
Clot Retraction ◽  
Interacting Protein ◽  
Bone Marrow Derived Cells

Previous studies have shown that receptor-interacting protein kinase 3 (RIP3) is involved in many important biological processes, including necroptosis, apoptosis, and inflammation. Here we show that RIP3 plays a critical role in regulating platelet functions and in vivo thrombosis and hemostasis. Tail bleeding times were significantly longer in RIP3-knockout (RIP3−/−) mice compared with their wild-type (WT) littermates. In an in vivo model of arteriole thrombosis, mice lacking RIP3 exhibited prolonged occlusion times. WT mice repopulated with RIP3−/− bone marrow-derived cells had longer occlusion times than RIP3−/− mice repopulated with WT bone marrow-derived cells, suggesting a role for RIP3-deficient platelets in arterial thrombosis. Consistent with these findings, we observed that RIP3 was expressed in both human and mice platelets. Deletion of RIP3 in mouse platelets caused a marked defect in aggregation and attenuated dense granule secretion in response to low doses of thrombin or a thromboxane A2 analog, U46619. Phosphorylation of Akt induced by U46619 or thrombin was diminished in RIP3−/− platelets. Moreover, RIP3 interacted with Gα13. Platelet spreading on fibrinogen and clot retraction were impaired in the absence of RIP3. RIP3 inhibitor dose-dependently inhibited platelet aggregation in vitro and prevented arterial thrombus formation in vivo. These data demonstrate a role for RIP3 in promoting in vivo thrombosis and hemostasis by amplifying platelet activation. RIP3 may represent a novel promising therapeutic target for thrombotic diseases.

scholarly journals The Dichotomous Role of Bone Marrow Derived Cells in the Chemotherapy-Treated Tumor Microenvironment

2020 ◽  
Vol 9 (12) ◽  
pp. 3912
Author(s):  
Avital Vorontsova ◽  
Tal Kan ◽  
Ziv Raviv ◽  
Yuval Shaked
Keyword(s):  
Bone Marrow ◽  
Tumor Microenvironment ◽  
Immune Modulation ◽  
Therapy Resistance ◽  
Therapy Outcomes ◽  
Primary Tumors ◽  
Combination Treatments ◽  
Response To Chemotherapy ◽  
Metastatic Process ◽  
Bone Marrow Derived Cells

Bone marrow derived cells (BMDCs) play a wide variety of pro- and anti-tumorigenic roles in the tumor microenvironment (TME) and in the metastatic process. In response to chemotherapy, the anti-tumorigenic function of BMDCs can be enhanced due to chemotherapy-induced immunogenic cell death. However, in recent years, a growing body of evidence suggests that chemotherapy or other anti-cancer drugs can also facilitate a pro-tumorigenic function in BMDCs. This includes elevated angiogenesis, tumor cell proliferation and pro-tumorigenic immune modulation, ultimately contributing to therapy resistance. Such effects do not only contribute to the re-growth of primary tumors but can also support metastasis. Thus, the delicate balance of BMDC activities in the TME is violated following tumor perturbation, further requiring a better understanding of the complex crosstalk between tumor cells and BMDCs. In this review, we discuss the different types of BMDCs that reside in the TME and their activities in tumors following chemotherapy, with a major focus on their pro-tumorigenic role. We also cover aspects of rationally designed combination treatments that target or manipulate specific BMDC types to improve therapy outcomes.

Abstract 2860: A critical role of bone marrow-derived cells for hedgehog-mediated carcinogenesis.

2013 ◽  
Author(s):  
Jingwu Xie ◽  
Eric Qipeng Fan ◽  
Dongsheng Gu ◽  
Hailan Liu ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Critical Role ◽  
Bone Marrow Derived Cells

scholarly journals Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses

2020 ◽  
Author(s):  
Xianda Zhao ◽  
Ce Yuan ◽  
Dechen Wangmo ◽  
Subbaya Subramanian
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Intrinsic Factors ◽  
Intravenous Injections ◽  
Stage Disease ◽  
Underlying Mechanisms ◽  
And Function

SUMMARYTumor intrinsic factors negatively regulate tumor immune cell infiltration and function. Deciphering the underlying mechanisms is critical to improving immunotherapy in cancers. Our analyses of human colorectal cancer (CRC) immune profiles and tumor-immune cell interactions revealed that tumor cell secreted extracellular vesicles (TEVs) induced immunosuppression in CRC. Specifically, TEVs containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory pathway in tumor infiltrating T cells and dendritic cells. Modified TEVs with miR-424 knocked down enhanced T-cell mediated antitumor immune response in CRC tumor models and increased the response to immune checkpoint blockade therapies (ICBT). Intravenous injections of modified TEVs induced tumor antigen specific immune responses. Moreover, injections of modified TEVs boosted the ICBT efficacy in CRC models that mimic treatment refractory late-stage disease. Collectively, we demonstrate a critical role for TEVs in antitumor immune regulation and immunotherapy response, which could be developed as a novel treatment for ICBT resistant human CRC.

scholarly journals Bone marrow derived extracellular vesicles activate osteoclast differentiation in traumatic brain injury induced bone loss

2018 ◽  
Author(s):  
Quante Singleton ◽  
Kumar Vaibhav ◽  
Molly Braun ◽  
Andrew Khayrullin ◽  
Bharati Mendhe ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Bone Loss ◽  
Extracellular Vesicles ◽  
Bone Marrow Cells ◽  
Bone Fractures ◽  
Osteoclast Differentiation ◽  
Bone Marrow Niche ◽  
Bone Marrow Derived Cells

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

DISTINCT ROLES FOR DISCOIDIN DOMAIN RECEPTOR 1 (DDR1) EXPRESSED ON BONE MARROW DERIVED CELLS AND VESSEL WALL CELLS DURINGATHEROGENESIS

2008 ◽  
Vol 31 (4) ◽  
pp. 10
Author(s):  
C Franco ◽  
G Hou ◽  
M P Bendeck
Keyword(s):  
Bone Marrow ◽  
Vessel Wall ◽  
Critical Role ◽  
Chimeric Mice ◽  
Lesion Area ◽  
Aortic Sinus ◽  
Discoidin Domain Receptor ◽  
Plaque Development ◽  
Bone Marrow Derived Cells ◽  
Discoidin Domain Receptor 1

We have recently described a critical role for the discoidin domain receptor 1 (DDR1) collagen receptor tyrosine kinase in the regulation of fibrosis and inflammation during atherosclerotic plaque development. DDR1 isexpressed on both SMCs and macrophages; however the role of DDR1 expressed in these distinct cells during atherogenesis remains unresolved. In the current study, female Ldlr^-/- mice that were either Ddr1^+/+ or Ddr1^-/-were lethally irradiated and reconstituted with bone marrow from male Ddr1^+/+ or Ddr1^-/- donors yielding three groups of chimeric mice: Ddr1^+/+^?^+/+ (control); Ddr1^+/+^?^-/-^ (vessel wall deletion); and Ddr1^-/-^?^+/+ (bone marrow deletion). Chimeric mice were placed on an atherogenic diet for 12 weeks and hadsimilar body weights, total leukocyte counts, levels of Sry chimerism, and fasting plasma triglycerides at sacrifice, although total cholesterol was increased by 42% in Ddr1^+/+^?^-/- mice. Deletion of DDR1 inbone marrow derived cells (Ddr1^-/-^?^+/+) resulted in a 66% reduction in atherosclerotic lesion area in thedescending aorta compared to Ddr1^+/+^?^+/+ mice. Aortic sinus plaquesfrom Ddr1^-/-^?^+/+ mice were 36% smaller than Ddr1^+/+^?^+/+ plaques but the proportion of plaque area occupied by cells and matrix was similar between groups. By contrast, deletion of DDR1 in vessel wall cells (Ddr1^+/+^?^-/-) resulted in a 57% increase in atherosclerosis in the descending aorta. Furthermore, aortic sinus plaques from Ddr1^+/+ ^?^-/- mice had markedly increased fibrillar collagen and elastin accumulation compared to Ddr1^+/+^?^+/+ plaques resulting in a 156% increase in lesion area and reduced SMC and macrophage content. In conclusion, while DDR1 on bone marrow derived cells is required for plaque development, DDR1 expressed on vessel wall cells negatively regulates plaque matrix accumulation and results in the formation of larger lesions with altered cellular composition. Our data suggest a dual role for DDR1 in the regulationof atherogenesis and plaque matrix content.

scholarly journals Bone Marrow Derived Extracellular Vesicles Activate Osteoclast Differentiation in Traumatic Brain Injury Induced Bone Loss

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 63 ◽  
Author(s):  
Quante Singleton ◽  
Kumar Vaibhav ◽  
Molly Braun ◽  
Chandani Patel ◽  
Andrew Khayrullin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Bone Loss ◽  
Extracellular Vesicles ◽  
Bone Fractures ◽  
Ex Vivo ◽  
Osteoclast Differentiation ◽  
Bone Marrow Niche ◽  
Bone Marrow Derived Cells

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in vivo CD-1 mice. Further, we identified dysregulated NF-κB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

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