Noninvasive Imaging Reveals Inhibition of Ovarian Cancer by Targeting CXCL12-CXCR4

Ray, Paramita; Lewin, Sarah A.; Mihalko, Laura Anne; Schmidt, Bradley T.; Luker, Gary D.

doi:10.1593/neo.111076

Cited by 37 publications

(26 citation statements)

References 31 publications

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“…In two separate studies involving mouse models of EOC, AMD3100 (a clinically approved CXCR4 inhibitor) significantly reduced ovarian cancer cell growth (Ray et al 2011, Righi et al 2011. In mice, administration of AMD3100 significantly reduced intraperitoneal dissemination and angiogenesis (measured by vessel density with the tumour), increased T-cell-mediated anti-tumour immune responses and apoptosis and reduced FoxP3 C T reg cell numbers within the tumour (Righi et al 2011).…”

Section: Chemokines As Future Therapeutic Targets For Eocmentioning

confidence: 99%

“…In mice, administration of AMD3100 significantly reduced intraperitoneal dissemination and angiogenesis (measured by vessel density with the tumour), increased T-cell-mediated anti-tumour immune responses and apoptosis and reduced FoxP3 C T reg cell numbers within the tumour (Righi et al 2011). Subsequently, it was shown that AMD3100 blocked CXCL12/CXCR4 binding, resulting in prolonged survival and reduced tumour growth in mice with disseminated ovarian cancer (Ray et al 2011). The use of this important chemokine inhibitor in human trials is yet to be reported.…”

Section: Chemokines As Future Therapeutic Targets For Eocmentioning

confidence: 99%

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The emerging role of CXC chemokines in epithelial ovarian cancer

et al. 2012

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In recent years, chemokines have generated intense investigations due to their involvement in both physiological and pathological processes of inflammation, particularly in ovarian biology. The physiological process of ovulation in the normal ovary involves various chemokines that mediate the healing of the ruptured endometrium. It is now being reported that many of these chemokines are also associated with the cancer of the ovary. Chronic inflammation underlies the progression of ovarian cancer; therefore, it raises the possibility that chemokines are involved in the inflammatory process and mediate immune responses that may favour or inhibit tumour progression. Ovarian cancer is a gynaecological cancer responsible for highest rate of mortality in women. Although there have been several investigations and advances in surgery and chemotherapy, the survival rate for this disease remains low. This is mainly because of a lack of specific symptoms and biomarkers for detection. In this review, we have discussed the emerging role of the CXC chemokines in epithelial ovarian cancer (EOC). The CXC group of chemokines is gaining importance in the field of ovarian cancer for being angiostatic and angiogenic in function. While there have been several studies on the angiogenesis function, emerging research shows that ELR K CXC chemokines, CXCL9 and CXCL10, are angiostatic. Importantly, the angiostatic chemokines can inhibit the progression of EOC. Given that there are currently no biomarkers or specific therapeutic targets for the disease, these chemokines are emerging as promising targets for therapy.

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Section: Chemokines As Future Therapeutic Targets For Eocmentioning

confidence: 99%

Section: Chemokines As Future Therapeutic Targets For Eocmentioning

confidence: 99%

The emerging role of CXC chemokines in epithelial ovarian cancer

et al. 2012

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“…In mouse models, we and others have shown that blocking CXCL12-CXCR4 signaling with RNA interference against CXCL12 or a small molecule inhibitor of CXCL12-CXCR4 binding (AMD3100) limits growth of ovarian cancer cell implants [12], [13], [14]. Inhibiting CXCL12-CXCR4 signaling also extends survival of mice with ovarian cancer.…”

Section: Introductionmentioning

confidence: 98%

Imaging CXCL12-CXCR4 Signaling in Ovarian Cancer Therapy

et al. 2013

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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.

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“…AMD3100 is a highly specific CXCR4 antagonist that has been shown to block CXCL12α action in cell-based assays and in living mice with disseminated ovarian cancer [30], and it is approved for clinical use. Mutational analysis of the CXCR4 receptor has shown that binding of AMD3100 is dependent on both Asp 171 and Asp 262 [31].…”

Section: Resultsmentioning

confidence: 99%

Quantification of Ligand Binding to G-Protein Coupled Receptors on Cell Membranes by Ellipsometry

et al. 2012

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G-protein-coupled receptors (GPCRs) are prime drug targets and targeted by approximately 60% of current therapeutic drugs such as β-blockers, antipsychotics and analgesics. However, no biophysical methods are available to quantify their interactions with ligand binding in a native environment. Here, we use ellipsometry to quantify specific interactions of receptors within native cell membranes. As a model system, the GPCR-ligand CXCL12α and its receptor CXCR4 are used. Human-derived Ishikawa cells were deposited onto gold coated slides via Langmuir-Schaefer film deposition and interactions between the receptor CXCR4 on these cells and its ligand CXCL12α were detected via total internal reflection ellipsometry (TIRE). This interaction could be inhibited by application of the CXCR4-binding drug AMD3100. Advantages of this approach are that it allows measurement of interactions in a lipid environment without the need for labelling, protein purification or reconstitution of membrane proteins. This technique is potentially applicable to a wide variety of cell types and their membrane receptors, providing a novel method to determine ligand or drug interactions targeting GPCRs and other membrane proteins.

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Noninvasive Imaging Reveals Inhibition of Ovarian Cancer by Targeting CXCL12-CXCR4

Cited by 37 publications

References 31 publications

The emerging role of CXC chemokines in epithelial ovarian cancer

The emerging role of CXC chemokines in epithelial ovarian cancer

Imaging CXCL12-CXCR4 Signaling in Ovarian Cancer Therapy

Quantification of Ligand Binding to G-Protein Coupled Receptors on Cell Membranes by Ellipsometry

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