Journal of the National Cancer Institute Advance Access published online on August 28, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm107
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Ovarian Cancer G Protein–Coupled Receptor 1, a New Metastasis Suppressor Gene in Prostate Cancer
Affiliations of authors: Department of Obstetrics and Gynecology, Indiana University, Indianapolis, IN (LSS, ZZ, KK, RS, YX); Department of Cancer Biology, Lerner Research Institute (LSS, MB, ZZ, HT, YJ, YX), Department of Drug Development, Taussig Cancer Center (RO, DL), Department of Obstetrics and Gynecology (YX), Cleveland Clinic, Cleveland, OH; Department of Chemistry, The Cleveland State University, Cleveland, OH (AZ)
Correspondence to: Yan Xu, PhD, Department of Obstetrics and Gynecology, Indiana University School of Medicine, 975 W. Walnut St IB355A, Indianapolis, IN 46202 (e-mail: xu2{at}iupui.edu).
Background: Metastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein–coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues.
Methods: We used an orthotopic mouse metastasis model, in which we injected PC3 metastatic human prostate cancer cells stably transfected with empty vector (vector-PC3) or OGR1-expressing vector (OGR1-PC3) into the prostate lobes of athymic or NOD/SCID mice (n = 3–8 mice per group). Migration of PC3 cells transiently transfected with vector control or with OGR1- or GPR4 (a G protein–coupled receptor with the highest homology to OGR1)-expressing vectors was measured in vitro by Boyden chamber assays. G protein alpha–inhibitory subunit 1 (G
i1) expression after treatment with pertussis toxin (PTX) was measured using immunoblotting analysis. The inhibitory factor present in the conditioned medium was extracted using organic solvents and analyzed by mass spectrometry.
Results: In vivo, all 26 mice carrying tumors that were derived from vector-PC3 cells developed prostate cancer metastases (mean = 100%, 95% confidence interval [CI] = 83.97% to 100%) but few (4 of 32) mice carrying tumors derived from OGR1-expressing PC3 cells (mean = 12.50%, 95% CI = 4.08% to 29.93%) developed metastases. However, exogenous OGR1 overexpression had no effect on primary prostate tumor growth in vivo. In vitro, expression of OGR1, but not GPR4, inhibited cell migration (mean percentage of cells migrated, 30.2% versus 100%, difference = 69.8%, 95% CI = 63.0% to 75.9%; P<.001) via increased expression of Gi1 and the secretion of a chloroform/methanol–extractable heat-insensitive factor into the conditioned medium through a PTX-sensitive pathway.
Conclusion: OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1's constitutive activity via Gi contributes to its inhibitory effect on cell migration in vitro.
| CONTEXT AND CAVEATS Prior knowledge Tumor metastasis is a major cause of death among cancer patients. The expression of ovarian cancer G protein–coupled receptor 1 (OGR1) is higher in primary prostate tumors than metastases. Study design Mouse models of prostate cancer metastasis and in vitro migration assays using control human prostate cancer cells and those engineered to overexpress OGR1. Contributions Cells overexpressing OGR1 formed fewer metastases in the mouse models and migrated more slowly in vitro than control cells. Implications OGR1 acts as a metastasis suppressor gene in prostate cancer. Study limitations Only one prostate cancer cell line was used in the mouse models. In these models, this cell line did not metastasize to bone, which is one of the most common sites of metastasis in prostate cancer as well as other types of cancer. Thus, how OGR1 might affect metastasis to bone is unknown, as is the application of these findings to human prostate cancer.
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Manuscript received April 21, 2007; revised June 25, 2007; accepted July 12, 2007.
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J Natl Cancer Inst 2007 99: 1277.
J Natl Cancer Inst 2007 99: 1277.
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