Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy

Huan Huan Wang, Yao Li Cui, Nicholas Zaorsky, Jie Lan, Lei Deng, Xian Liang Zeng, Zhi Qiang Wu, Zhen Tao, Wen Hao Guo, Qing Xin Wang, Lu Jun Zhao, Zhi Yong Yuan, You Lu, Ping Wang, Mao Bin Meng

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. Methods: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. Results: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. Conclusion: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

Original languageEnglish (US)
Pages (from-to)349-359
Number of pages11
JournalCancer Letters
Volume375
Issue number2
DOIs
StatePublished - Jun 1 2016

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Pericytes
Mesenchymal Stromal Cells
Radiotherapy
Recurrence
Neoplasms
Bone Marrow
Cell Movement
CCR Receptors
Proto-Oncogene Proteins c-sis
Lewis Lung Carcinoma
Chemokine CXCL12
Platelet-Derived Growth Factor Receptors
Tumor Microenvironment
Green Fluorescent Proteins
Bone Marrow Transplantation
Transgenic Mice
Cell Differentiation
Melanoma

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wang, Huan Huan ; Cui, Yao Li ; Zaorsky, Nicholas ; Lan, Jie ; Deng, Lei ; Zeng, Xian Liang ; Wu, Zhi Qiang ; Tao, Zhen ; Guo, Wen Hao ; Wang, Qing Xin ; Zhao, Lu Jun ; Yuan, Zhi Yong ; Lu, You ; Wang, Ping ; Meng, Mao Bin. / Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy. In: Cancer Letters. 2016 ; Vol. 375, No. 2. pp. 349-359.
@article{7838f08f9c6f41178f45c64375307462,
title = "Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy",
abstract = "Background: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. Methods: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. Results: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. Conclusion: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.",
author = "Wang, {Huan Huan} and Cui, {Yao Li} and Nicholas Zaorsky and Jie Lan and Lei Deng and Zeng, {Xian Liang} and Wu, {Zhi Qiang} and Zhen Tao and Guo, {Wen Hao} and Wang, {Qing Xin} and Zhao, {Lu Jun} and Yuan, {Zhi Yong} and You Lu and Ping Wang and Meng, {Mao Bin}",
year = "2016",
month = "6",
day = "1",
doi = "10.1016/j.canlet.2016.02.033",
language = "English (US)",
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pages = "349--359",
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Wang, HH, Cui, YL, Zaorsky, N, Lan, J, Deng, L, Zeng, XL, Wu, ZQ, Tao, Z, Guo, WH, Wang, QX, Zhao, LJ, Yuan, ZY, Lu, Y, Wang, P & Meng, MB 2016, 'Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy', Cancer Letters, vol. 375, no. 2, pp. 349-359. https://doi.org/10.1016/j.canlet.2016.02.033

Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy. / Wang, Huan Huan; Cui, Yao Li; Zaorsky, Nicholas; Lan, Jie; Deng, Lei; Zeng, Xian Liang; Wu, Zhi Qiang; Tao, Zhen; Guo, Wen Hao; Wang, Qing Xin; Zhao, Lu Jun; Yuan, Zhi Yong; Lu, You; Wang, Ping; Meng, Mao Bin.

In: Cancer Letters, Vol. 375, No. 2, 01.06.2016, p. 349-359.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy

AU - Wang, Huan Huan

AU - Cui, Yao Li

AU - Zaorsky, Nicholas

AU - Lan, Jie

AU - Deng, Lei

AU - Zeng, Xian Liang

AU - Wu, Zhi Qiang

AU - Tao, Zhen

AU - Guo, Wen Hao

AU - Wang, Qing Xin

AU - Zhao, Lu Jun

AU - Yuan, Zhi Yong

AU - Lu, You

AU - Wang, Ping

AU - Meng, Mao Bin

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. Methods: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. Results: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. Conclusion: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

AB - Background: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. Methods: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. Results: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. Conclusion: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

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U2 - 10.1016/j.canlet.2016.02.033

DO - 10.1016/j.canlet.2016.02.033

M3 - Article

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AN - SCOPUS:84962599677

VL - 375

SP - 349

EP - 359

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 2

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