Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration

John Karavitis, Laura M. Hix, Yihui H. Shi, Rachael F. Schultz, Khashayarsha Khazaie, Ming Zhang

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune-competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. Methodology/Principal Findings: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. Conclusion/Significance: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression.

Original languageEnglish (US)
Article numbere46342
JournalPLoS One
Volume7
Issue number9
DOIs
StatePublished - Sep 28 2012
Externally publishedYes

Fingerprint

T-cells
mammary neoplasms (animal)
prostaglandin synthase
Regulatory T-Lymphocytes
Cyclooxygenase 2
cell movement
Dinoprostone
metastasis
prostaglandins
Cell Movement
Tumors
Bone
T-lymphocytes
Cells
bones
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
breast neoplasms
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration. / Karavitis, John; Hix, Laura M.; Shi, Yihui H.; Schultz, Rachael F.; Khazaie, Khashayarsha; Zhang, Ming.

In: PLoS One, Vol. 7, No. 9, e46342, 28.09.2012.

Research output: Contribution to journalArticle

Karavitis, John ; Hix, Laura M. ; Shi, Yihui H. ; Schultz, Rachael F. ; Khazaie, Khashayarsha ; Zhang, Ming. / Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration. In: PLoS One. 2012 ; Vol. 7, No. 9.
@article{47045c52616e4445963bd9d5efe6031e,
title = "Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration",
abstract = "Background: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune-competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. Methodology/Principal Findings: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. Conclusion/Significance: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression.",
author = "John Karavitis and Hix, {Laura M.} and Shi, {Yihui H.} and Schultz, {Rachael F.} and Khashayarsha Khazaie and Ming Zhang",
year = "2012",
month = "9",
day = "28",
doi = "10.1371/journal.pone.0046342",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration

AU - Karavitis, John

AU - Hix, Laura M.

AU - Shi, Yihui H.

AU - Schultz, Rachael F.

AU - Khazaie, Khashayarsha

AU - Zhang, Ming

PY - 2012/9/28

Y1 - 2012/9/28

N2 - Background: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune-competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. Methodology/Principal Findings: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. Conclusion/Significance: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression.

AB - Background: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune-competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. Methodology/Principal Findings: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. Conclusion/Significance: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression.

UR - http://www.scopus.com/inward/record.url?scp=84867031414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867031414&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0046342

DO - 10.1371/journal.pone.0046342

M3 - Article

C2 - 23029485

AN - SCOPUS:84867031414

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e46342

ER -