Imaging CXCL12-CXCR4 signaling in ovarian cancer therapy

Emma Salomonnson; Amanda C Stacer; Anna Ehrlich; Kathryn E Luker; Gary D Luker

doi:10.1371/journal.pone.0051500

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Imaging CXCL12-CXCR4 signaling in ovarian cancer therapy

Journal article

Open access

Peer reviewed

Imaging CXCL12-CXCR4 signaling in ovarian cancer therapy

Emma Salomonnson, Amanda C Stacer, Anna Ehrlich, Kathryn E Luker and Gary D Luker

PloS one, Vol.8(1), pp.e51500-e51500

01/23/2013

DOI: 10.1371/journal.pone.0051500

PMCID: PMC3553093

PMID: 23372646

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Abstract

Chemokine CXCL12 and receptor CXCR4 have emerged as promising therapeutic targets for ovarian cancer, a disease that continues to have a dismal prognosis. CXCL12-CXCR4 signaling drives proliferation, survival, and invasion of ovarian cancer cells, leading to tumor growth and metastasis. Pleiotropic effects of CXCR4 in multiple key steps in ovarian cancer suggest that blocking this pathway will improve outcomes for patients with this disease. To quantify CXCL12-CXCR4 signaling in cell-based assays and living mouse models of ovarian cancer, we developed a click beetle red luciferase complementation reporter that detects activation of CXCR4 based on recruitment of the cytosolic adapter protein β-arrestin 2. Both in two-dimensional and three-dimensional cell cultures, we established that bioluminescence from this reporter measures CXCL12-dependent activation of CXCR4 and inhibition of this pathway with AMD3100, a clinically-approved small molecule that blocks CXCL12-CXCR4 binding. We used this imaging system to quantify CXCL12-CXCR4 signaling in a mouse model of metastatic ovarian cancer and showed that treatment with AMD3100 interrupted this pathway in vivo. Combination therapy with AMD3100 and cisplatin significantly decreased tumor burden in mice, although differences in overall survival were not significantly greater than treatment with either agent as monotherapy. These studies establish a molecular imaging reporter system for analyzing CXCL12-CXCR4 signaling in ovarian cancer, which can be used to investigate biology and therapeutic targeting of this pathway in cell-based assays and living mice.

Animals

Antineoplastic Agents - pharmacology

Arrestins - genetics

Arrestins - metabolism

beta-Arrestin 2

beta-Arrestins

Cell Line, Tumor

Cell Proliferation

Chemokine CXCL12 - genetics

Chemokine CXCL12 - metabolism

Cisplatin - pharmacology

Female

Gene Expression Regulation, Neoplastic - drug effects

Genes, Reporter

Heterocyclic Compounds - pharmacology

Humans

Luciferases

Luminescent Measurements

Mice

Mice, SCID

Molecular Imaging - methods

Neoplasm Transplantation

Ovarian Neoplasms - drug therapy

Ovarian Neoplasms - genetics

Ovarian Neoplasms - metabolism

Ovarian Neoplasms - pathology

Receptors, CXCR4 - antagonists & inhibitors

Receptors, CXCR4 - genetics

Receptors, CXCR4 - metabolism

Signal Transduction - drug effects

Details

Title: Subtitle: Imaging CXCL12-CXCR4 signaling in ovarian cancer therapy
Creators: Emma Salomonnson - University of Michigan–Ann Arbor
Amanda C Stacer - University of Michigan–Ann Arbor
Anna Ehrlich - University of Michigan–Ann Arbor
Kathryn E Luker - University of Michigan–Ann Arbor
Gary D Luker - University of Michigan–Ann Arbor
Resource Type: Journal article
Publication Details: PloS one, Vol.8(1), pp.e51500-e51500
DOI: 10.1371/journal.pone.0051500
PMID: 23372646
PMCID: PMC3553093
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: R01CA136553 / NCI NIH HHS R01CA136829 / NCI NIH HHS P50CA093990 / NCI NIH HHS P50 CA093990 / NCI NIH HHS R01 CA136829 / NCI NIH HHS R01 CA136553 / NCI NIH HHS
Language: English
Date published: 01/23/2013
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984696761802771

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