Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells: Journal of Bone and Mineral Research

A. Loftus; A. Cappariello; C. George; A. Ucci; K. Shefferd; A. Green; R. Paone; M. Ponzetti; S. Delle Monache; M. Muraca; A. Teti; N. Rucci

doi:10.1002/jbmr.3891

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells: Journal of Bone and Mineral Research

A. Loftus, A. Cappariello, C. George, A. Ucci, K. Shefferd, A. Green, R. Paone, M. Ponzetti, S. Delle Monache, M. Muraca, A. Teti, N. Rucci

Research output: Contribution to journal › Article › peer-review

Abstract

Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research

Original language	English
Pages (from-to)	396-412
Number of pages	17
Journal	J. Bone Miner. Res.
Volume	35
Issue number	2
DOIs	https://doi.org/10.1002/jbmr.3891
Publication status	Published - 2020

Keywords

CANCER
CELL/TISSUE SIGNALING - ENDOCRINE PATHWAYS
CELL/TISSUE SIGNALING - PARACRINE PATHWAYS
CELLS OF BONE
CYTOKINES
OSTEOBLASTS
OSTEOCLASTS
OTHER
TUMOR-INDUCED BONE DISEASE
alkaline phosphatase
angiopoietin 2
collagen 1a1
collagen type 1
cutaneous T cell attracting chemokine
CXCL2 chemokine
cyclin D1
estrogen receptor
gamma interferon inducible protein 10
inducible nitric oxide synthase
interleukin 1beta
interleukin 6
macrophage inflammatory protein 1alpha
macrophage inflammatory protein 3alpha
messenger RNA
neutrophil gelatinase associated lipocalin
osteocalcin
osteoclast differentiation factor
pancreatitis associated protein
platelet derived growth factor BB
transcription factor osterix
transcription factor RUNX2
transforming growth factor beta1
unclassified drug
vasculotropin
4T1 cell line
angiogenesis
animal experiment
animal model
animal tissue
Article
bone cell
bone metabolism
breast cancer
cell count
cell differentiation
chondrocyte
comparative study
controlled study
cytokine release
down regulation
endothelium cell
enzyme activity
enzyme linked immunosorbent assay
ex vivo study
exosome
female
histochemistry
human
human cell
in vitro study
in vivo study
male
mouse
mRNA expression level
MTT assay
nonhuman
osteoblast
osteoclast
osteoclastogenesis
osteoporosis
transmission electron microscopy
Western blotting

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Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells : Journal of Bone and Mineral Research. / Loftus, A.; Cappariello, A.; George, C.; Ucci, A.; Shefferd, K.; Green, A.; Paone, R.; Ponzetti, M.; Delle Monache, S.; Muraca, M.; Teti, A.; Rucci, N.

In: J. Bone Miner. Res., Vol. 35, No. 2, 2020, p. 396-412.

Research output: Contribution to journal › Article › peer-review

@article{e06bc9b1ea2546e7938738f57869a83f,

title = "Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells: Journal of Bone and Mineral Research",

abstract = "Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. {\textcopyright} 2019 American Society for Bone and Mineral Research. {\textcopyright} 2019 American Society for Bone and Mineral Research",

keywords = "CANCER, CELL/TISSUE SIGNALING - ENDOCRINE PATHWAYS, CELL/TISSUE SIGNALING - PARACRINE PATHWAYS, CELLS OF BONE, CYTOKINES, OSTEOBLASTS, OSTEOCLASTS, OTHER, TUMOR-INDUCED BONE DISEASE, alkaline phosphatase, angiopoietin 2, collagen 1a1, collagen type 1, cutaneous T cell attracting chemokine, CXCL2 chemokine, cyclin D1, estrogen receptor, gamma interferon inducible protein 10, inducible nitric oxide synthase, interleukin 1beta, interleukin 6, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 3alpha, messenger RNA, neutrophil gelatinase associated lipocalin, osteocalcin, osteoclast differentiation factor, pancreatitis associated protein, platelet derived growth factor BB, transcription factor osterix, transcription factor RUNX2, transforming growth factor beta1, unclassified drug, vasculotropin, 4T1 cell line, angiogenesis, animal experiment, animal model, animal tissue, Article, bone cell, bone metabolism, breast cancer, cell count, cell differentiation, chondrocyte, comparative study, controlled study, cytokine release, down regulation, endothelium cell, enzyme activity, enzyme linked immunosorbent assay, ex vivo study, exosome, female, histochemistry, human, human cell, in vitro study, in vivo study, male, mouse, mRNA expression level, MTT assay, nonhuman, osteoblast, osteoclast, osteoclastogenesis, osteoporosis, transmission electron microscopy, Western blotting",

author = "A. Loftus and A. Cappariello and C. George and A. Ucci and K. Shefferd and A. Green and R. Paone and M. Ponzetti and {Delle Monache}, S. and M. Muraca and A. Teti and N. Rucci",

note = "Cited By :5 Export Date: 19 March 2021 CODEN: JBMRE Correspondence Address: Rucci, N.; Department of Biotechnological and Applied Clinical Sciences, Italy; email: rucci@univaq.it",

year = "2020",

doi = "10.1002/jbmr.3891",

language = "English",

volume = "35",

pages = "396--412",

journal = "J. Bone Miner. Res.",

issn = "0884-0431",

publisher = "John Wiley and Sons Inc.",

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TY - JOUR

T1 - Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

T2 - Journal of Bone and Mineral Research

AU - Loftus, A.

AU - Cappariello, A.

AU - George, C.

AU - Ucci, A.

AU - Shefferd, K.

AU - Green, A.

AU - Paone, R.

AU - Ponzetti, M.

AU - Delle Monache, S.

AU - Muraca, M.

AU - Teti, A.

AU - Rucci, N.

N1 - Cited By :5 Export Date: 19 March 2021 CODEN: JBMRE Correspondence Address: Rucci, N.; Department of Biotechnological and Applied Clinical Sciences, Italy; email: rucci@univaq.it

PY - 2020

Y1 - 2020

N2 - Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research

AB - Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research

KW - CANCER

KW - CELL/TISSUE SIGNALING - ENDOCRINE PATHWAYS

KW - CELL/TISSUE SIGNALING - PARACRINE PATHWAYS

KW - CELLS OF BONE

KW - CYTOKINES

KW - OSTEOBLASTS

KW - OSTEOCLASTS

KW - OTHER

KW - TUMOR-INDUCED BONE DISEASE

KW - alkaline phosphatase

KW - angiopoietin 2

KW - collagen 1a1

KW - collagen type 1

KW - cutaneous T cell attracting chemokine

KW - CXCL2 chemokine

KW - cyclin D1

KW - estrogen receptor

KW - gamma interferon inducible protein 10

KW - inducible nitric oxide synthase

KW - interleukin 1beta

KW - interleukin 6

KW - macrophage inflammatory protein 1alpha

KW - macrophage inflammatory protein 3alpha

KW - messenger RNA

KW - neutrophil gelatinase associated lipocalin

KW - osteocalcin

KW - osteoclast differentiation factor

KW - pancreatitis associated protein

KW - platelet derived growth factor BB

KW - transcription factor osterix

KW - transcription factor RUNX2

KW - transforming growth factor beta1

KW - unclassified drug

KW - vasculotropin

KW - 4T1 cell line

KW - angiogenesis

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - bone cell

KW - bone metabolism

KW - breast cancer

KW - cell count

KW - cell differentiation

KW - chondrocyte

KW - comparative study

KW - controlled study

KW - cytokine release

KW - down regulation

KW - endothelium cell

KW - enzyme activity

KW - enzyme linked immunosorbent assay

KW - ex vivo study

KW - exosome

KW - female

KW - histochemistry

KW - human

KW - human cell

KW - in vitro study

KW - in vivo study

KW - male

KW - mouse

KW - mRNA expression level

KW - MTT assay

KW - nonhuman

KW - osteoblast

KW - osteoclast

KW - osteoclastogenesis

KW - osteoporosis

KW - transmission electron microscopy

KW - Western blotting

U2 - 10.1002/jbmr.3891

DO - 10.1002/jbmr.3891

M3 - Article

VL - 35

SP - 396

EP - 412

JO - J. Bone Miner. Res.

JF - J. Bone Miner. Res.

SN - 0884-0431

IS - 2

ER -

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells: Journal of Bone and Mineral Research

Abstract

Keywords

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