Solid tumor therapy by selectively targeting stromal endothelial cells

Shihui Liu, Jie Liu, Qian Ma, Liu Cao, Rasem J. Fattah, Zuxi Yu, Thomas H. Bugge, Toren Finkel, Stephen H. Leppla

Research output: Contribution to journalArticle

Abstract

Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

Original languageEnglish (US)
Pages (from-to)E4079-E4087
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number28
DOIs
StatePublished - Jul 12 2016
Externally publishedYes

Fingerprint

Stromal Cells
Endothelial Cells
Neoplasms
Therapeutics
Tumor Biomarkers
Morphogenesis
Endothelium
Proteins
Genetic Models
Immunosuppressive Agents
Growth

Keywords

  • Angiogenesis
  • Anthrax toxin
  • CMG2
  • TEM8
  • Tumor targeting

ASJC Scopus subject areas

  • General

Cite this

Solid tumor therapy by selectively targeting stromal endothelial cells. / Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J.; Yu, Zuxi; Bugge, Thomas H.; Finkel, Toren; Leppla, Stephen H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 28, 12.07.2016, p. E4079-E4087.

Research output: Contribution to journalArticle

Liu, S, Liu, J, Ma, Q, Cao, L, Fattah, RJ, Yu, Z, Bugge, TH, Finkel, T & Leppla, SH 2016, 'Solid tumor therapy by selectively targeting stromal endothelial cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 28, pp. E4079-E4087. https://doi.org/10.1073/pnas.1600982113
Liu, Shihui ; Liu, Jie ; Ma, Qian ; Cao, Liu ; Fattah, Rasem J. ; Yu, Zuxi ; Bugge, Thomas H. ; Finkel, Toren ; Leppla, Stephen H. / Solid tumor therapy by selectively targeting stromal endothelial cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 28. pp. E4079-E4087.
@article{303a3da46f1b44c88759230a343a7b9c,
title = "Solid tumor therapy by selectively targeting stromal endothelial cells",
abstract = "Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.",
keywords = "Angiogenesis, Anthrax toxin, CMG2, TEM8, Tumor targeting",
author = "Shihui Liu and Jie Liu and Qian Ma and Liu Cao and Fattah, {Rasem J.} and Zuxi Yu and Bugge, {Thomas H.} and Toren Finkel and Leppla, {Stephen H.}",
year = "2016",
month = "7",
day = "12",
doi = "10.1073/pnas.1600982113",
language = "English (US)",
volume = "113",
pages = "E4079--E4087",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "28",

}

TY - JOUR

T1 - Solid tumor therapy by selectively targeting stromal endothelial cells

AU - Liu, Shihui

AU - Liu, Jie

AU - Ma, Qian

AU - Cao, Liu

AU - Fattah, Rasem J.

AU - Yu, Zuxi

AU - Bugge, Thomas H.

AU - Finkel, Toren

AU - Leppla, Stephen H.

PY - 2016/7/12

Y1 - 2016/7/12

N2 - Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

AB - Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

KW - Angiogenesis

KW - Anthrax toxin

KW - CMG2

KW - TEM8

KW - Tumor targeting

UR - http://www.scopus.com/inward/record.url?scp=84978174643&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978174643&partnerID=8YFLogxK

U2 - 10.1073/pnas.1600982113

DO - 10.1073/pnas.1600982113

M3 - Article

C2 - 27357689

AN - SCOPUS:84978174643

VL - 113

SP - E4079-E4087

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 28

ER -