Characterization of the CXCR4 signaling in pancreatic cancer cells

Daniel D Billadeau, Subrha Chatterjee, Patricia Bramati, Raghavakaimal Sreekumar, Vijay Shah, Karen Elaine Hedin, Raul Urrutia

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.

Original languageEnglish (US)
Pages (from-to)110-119
Number of pages10
JournalInternational Journal of Gastrointestinal Cancer
Volume37
Issue number4
DOIs
StatePublished - Dec 2006

Fingerprint

Pancreatic Neoplasms
CXCR4 Receptors
Neoplasm Metastasis
src-Family Kinases
MAP Kinase Signaling System
Matrix Metalloproteinases
Interleukin-8
Phosphatidylinositol 3-Kinases
Heterografts
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Endothelial Cells
Clinical Trials
Breast Neoplasms
Growth
Pharmaceutical Preparations
Genes
Neoplasms

Keywords

  • Angiogenesis
  • CXCL12
  • CXCR4
  • ERK
  • Pancreatic cancer

ASJC Scopus subject areas

  • Gastroenterology
  • Endocrinology
  • Oncology

Cite this

Characterization of the CXCR4 signaling in pancreatic cancer cells. / Billadeau, Daniel D; Chatterjee, Subrha; Bramati, Patricia; Sreekumar, Raghavakaimal; Shah, Vijay; Hedin, Karen Elaine; Urrutia, Raul.

In: International Journal of Gastrointestinal Cancer, Vol. 37, No. 4, 12.2006, p. 110-119.

Research output: Contribution to journalArticle

Billadeau, Daniel D ; Chatterjee, Subrha ; Bramati, Patricia ; Sreekumar, Raghavakaimal ; Shah, Vijay ; Hedin, Karen Elaine ; Urrutia, Raul. / Characterization of the CXCR4 signaling in pancreatic cancer cells. In: International Journal of Gastrointestinal Cancer. 2006 ; Vol. 37, No. 4. pp. 110-119.
@article{d504e6ae709c45c991cbbdd9fec3fd3c,
title = "Characterization of the CXCR4 signaling in pancreatic cancer cells",
abstract = "CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.",
keywords = "Angiogenesis, CXCL12, CXCR4, ERK, Pancreatic cancer",
author = "Billadeau, {Daniel D} and Subrha Chatterjee and Patricia Bramati and Raghavakaimal Sreekumar and Vijay Shah and Hedin, {Karen Elaine} and Raul Urrutia",
year = "2006",
month = "12",
doi = "10.1007/s12029-007-0011-7",
language = "English (US)",
volume = "37",
pages = "110--119",
journal = "Journal of Gastrointestinal Cancer",
issn = "1941-6628",
publisher = "Humana Press",
number = "4",

}

TY - JOUR

T1 - Characterization of the CXCR4 signaling in pancreatic cancer cells

AU - Billadeau, Daniel D

AU - Chatterjee, Subrha

AU - Bramati, Patricia

AU - Sreekumar, Raghavakaimal

AU - Shah, Vijay

AU - Hedin, Karen Elaine

AU - Urrutia, Raul

PY - 2006/12

Y1 - 2006/12

N2 - CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.

AB - CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.

KW - Angiogenesis

KW - CXCL12

KW - CXCR4

KW - ERK

KW - Pancreatic cancer

UR - http://www.scopus.com/inward/record.url?scp=43149117047&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43149117047&partnerID=8YFLogxK

U2 - 10.1007/s12029-007-0011-7

DO - 10.1007/s12029-007-0011-7

M3 - Article

C2 - 18175225

AN - SCOPUS:43149117047

VL - 37

SP - 110

EP - 119

JO - Journal of Gastrointestinal Cancer

JF - Journal of Gastrointestinal Cancer

SN - 1941-6628

IS - 4

ER -