Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling

Shaogang Sun; Song Chen; Fei Liu; Haige Wu; Jonathan McHugh; Ingrid L. Bergin; Anita Gupta; Denise Adams; Jun Lin Guan

doi:10.1016/j.ccell.2015.10.004

Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling

Shaogang Sun, Song Chen, Fei Liu, Haige Wu, Jonathan McHugh, Ingrid L. Bergin, Anita Gupta, Denise Adams, Jun Lin Guan^*

^*Corresponding author for this work

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

51 Scopus citations

Abstract

Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.

Original language	English (US)
Pages (from-to)	758-772
Number of pages	15
Journal	Cancer cell
Volume	28
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2015.10.004
State	Published - Dec 14 2015
Externally published	Yes

Funding

We are grateful to Dr. D.J. Kwiatkowski for Tsc1f/f mice and Dr. G. Begley for End-Scl-Cre-ERT transgenic mice. We thank the MicroCT Core and the Center for Molecular Imaging at the University of Michigan for microCT and MRI; A. Serna and J. Wen for assistance, our colleagues Drs. C. Wang, S. Yeo, and J. Wen for discussions, help, and comments; Drs. M. Czyzyk-Krzeska, D. Plas, E. Boscolo, and L. Chow for critical reading of the manuscript and insightful suggestions; G. Doerman for preparing figures; and Dr. B. Peace for editing. This research was supported by NIH grants HL073394, CA163493, and CA150926 to J.-L.G.; and AR062030 and DE021718 to F.L. We are grateful to Dr. D.J. Kwiatkowski for Tsc1 f/f mice and Dr. G. Begley for End-Scl-Cre-ER T transgenic mice. We thank the MicroCT Core and the Center for Molecular Imaging at the University of Michigan for microCT and MRI; A. Serna and J. Wen for assistance, our colleagues Drs. C. Wang, S. Yeo, and J. Wen for discussions, help, and comments; Drs. M. Czyzyk-Krzeska, D. Plas, E. Boscolo, and L. Chow for critical reading of the manuscript and insightful suggestions; G. Doerman for preparing figures; and Dr. B. Peace for editing. This research was supported by NIH grants HL073394, CA163493, and CA150926 to J.-L.G.; and AR062030 and DE021718 to F.L.

Keywords

Angiosarcoma
Lymphangiosarcoma
MTORC1 signaling
Mouse models
VEGF
Vascular anomalies
Vascular tumor

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2015.10.004

Cite this

@article{866bd15156be4ce2aa3a5f6ded746b30,

title = "Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling",

abstract = "Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.",

keywords = "Angiosarcoma, Lymphangiosarcoma, MTORC1 signaling, Mouse models, VEGF, Vascular anomalies, Vascular tumor",

author = "Shaogang Sun and Song Chen and Fei Liu and Haige Wu and Jonathan McHugh and Bergin, {Ingrid L.} and Anita Gupta and Denise Adams and Guan, {Jun Lin}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = dec,

day = "14",

doi = "10.1016/j.ccell.2015.10.004",

language = "English (US)",

volume = "28",

pages = "758--772",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling

AU - Sun, Shaogang

AU - Chen, Song

AU - Liu, Fei

AU - Wu, Haige

AU - McHugh, Jonathan

AU - Bergin, Ingrid L.

AU - Gupta, Anita

AU - Adams, Denise

AU - Guan, Jun Lin

PY - 2015/12/14

Y1 - 2015/12/14

N2 - Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.

AB - Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.

KW - Angiosarcoma

KW - Lymphangiosarcoma

KW - MTORC1 signaling

KW - Mouse models

KW - VEGF

KW - Vascular anomalies

KW - Vascular tumor

UR - http://www.scopus.com/inward/record.url?scp=84959088866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959088866&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2015.10.004

DO - 10.1016/j.ccell.2015.10.004

M3 - Article

C2 - 26777415

AN - SCOPUS:84959088866

SN - 1535-6108

VL - 28

SP - 758

EP - 772

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this