Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Sarah J. Conley, Elizabeth Gheordunescu, Pramod Kakarala, Bryan Newman, Hasan Korkaya, Amber N. Heath, Shawn G. Clouthier, Max S. Wicha

Research output: Contribution to journalArticle

378 Citations (Scopus)

Abstract

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

Original languageEnglish (US)
Pages (from-to)2784-2789
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
StatePublished - Feb 21 2012
Externally publishedYes

Fingerprint

Angiogenesis Inhibitors
Neoplastic Stem Cells
Breast Neoplasms
Heterografts
Stem Cells
Hypoxia-Inducible Factor 1
Catenins
Proxy
Drug Delivery Systems
Clinical Trials
Survival
Tumor Hypoxia
Therapeutics
Research
Population
Hypoxia
Neoplasms
sunitinib
In Vitro Techniques

Keywords

  • Antiangiogenesis
  • HIF-1α

ASJC Scopus subject areas

  • General

Cite this

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. / Conley, Sarah J.; Gheordunescu, Elizabeth; Kakarala, Pramod; Newman, Bryan; Korkaya, Hasan; Heath, Amber N.; Clouthier, Shawn G.; Wicha, Max S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 8, 21.02.2012, p. 2784-2789.

Research output: Contribution to journalArticle

Conley, Sarah J. ; Gheordunescu, Elizabeth ; Kakarala, Pramod ; Newman, Bryan ; Korkaya, Hasan ; Heath, Amber N. ; Clouthier, Shawn G. ; Wicha, Max S. / Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 8. pp. 2784-2789.
@article{1df9914dbffe45ba8ef354521f6de76b,
title = "Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia",
abstract = "Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.",
keywords = "Antiangiogenesis, HIF-1α",
author = "Conley, {Sarah J.} and Elizabeth Gheordunescu and Pramod Kakarala and Bryan Newman and Hasan Korkaya and Heath, {Amber N.} and Clouthier, {Shawn G.} and Wicha, {Max S.}",
year = "2012",
month = "2",
day = "21",
doi = "10.1073/pnas.1018866109",
language = "English (US)",
volume = "109",
pages = "2784--2789",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "8",

}

TY - JOUR

T1 - Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

AU - Conley, Sarah J.

AU - Gheordunescu, Elizabeth

AU - Kakarala, Pramod

AU - Newman, Bryan

AU - Korkaya, Hasan

AU - Heath, Amber N.

AU - Clouthier, Shawn G.

AU - Wicha, Max S.

PY - 2012/2/21

Y1 - 2012/2/21

N2 - Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

AB - Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

KW - Antiangiogenesis

KW - HIF-1α

UR - http://www.scopus.com/inward/record.url?scp=84857407549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857407549&partnerID=8YFLogxK

U2 - 10.1073/pnas.1018866109

DO - 10.1073/pnas.1018866109

M3 - Article

VL - 109

SP - 2784

EP - 2789

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 - 8

ER -