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Published on: November 28, 2015
Formylpeptide receptor FPR and the rapid growth of malignant human gliomas
Ye Zhou1, Xiuwu Bian, Yingying Le
1Laboratory of Molecular Immunoregulation, CCR, NCI-Frederick, Building 560, Room 31-40, Frederick, MD 21702-1201, USA.
Background:
The formylpeptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis of phagocytic leukocytes induced by bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). We previously showed that selected human glioma cell lines also express functional FPR. We therefore investigated the relationship between FPR expression and the biologic behavior of glioma cells.
Methods:
Expression and function of FPR in the human glioblastoma cell line U-87 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and chemotaxis assays, respectively. FPR protein expression was detected in specimens from 33 human primary gliomas by immunohistochemistry. FPR short interfering (si) RNA was used to block FPR expression in U-87 cells. Cell proliferation was assessed by measuring DNA synthesis. Xenograft tumor formation and growth were measured in nude mice. Endogenous FPR agonist activity released by necrotic tumor cells was assessed by measuring FPR activation in an FPR-transfected basophil leukemia cell line and live U-87 cells. Vascular endothelial growth factor (VEGF) mRNA was assessed by RT-PCR, and VEGF protein was assessed by enzyme-linked immunosorbent assay. All statistical tests were two-sided.
Results:
FPR was selectively expressed by the highly malignant human glioblastoma cell line U-87 and most primary grade IV glioblastomas multiforme and grade III anaplastic astrocytomas. U-87 cells responded to the FPR agonist fMLF by chemotaxis (i.e., increased motility), increased cell proliferation, and increased production of VEGF protein. FPR siRNA substantially reduced the tumorigenicity of U-87 cells in nude mice (38 days after implantation, mean tumor volume from wild-type U-87 cells = 842 mm3, 95% confidence interval [CI] = 721 to 963 mm3; and from FPR-siRNA transfected U-87 cells = 225 mm3, 95% CI = 194 to 256 mm3; P = .001). Necrotic glioblastoma cells released a factor(s) that activated FPR in live U-87 cells.
Conclusions:
FPR is expressed by highly malignant human glioma cells and appears to mediate motility, growth, and angiogenesis of human glioblastoma by interacting with host-derived agonists. Thus, FPR may represent a molecular target for the development of novel antiglioma therapeutics.
Insights
Formylpeptide receptor (FPR) is expressed in aggressive gliomas, driving tumor growth and motility. Blocking FPR significantly reduced glioblastoma tumor formation, suggesting FPR as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- The formylpeptide receptor (FPR) is a G-protein-coupled receptor (GPCR) crucial for leukocyte chemotaxis.
- Previous research indicated functional FPR expression in certain human glioma cell lines.
- This study investigates the role of FPR in glioma cell behavior.
Purpose of the Study:
- To examine the expression and function of FPR in glioblastoma.
- To determine the relationship between FPR and glioma cell proliferation, motility, and angiogenesis.
- To evaluate FPR as a potential therapeutic target for glioblastoma.
Main Methods:
- FPR expression and function were assessed in U-87 glioblastoma cells using RT-PCR and chemotaxis assays.
- Immunohistochemistry was used to detect FPR in human glioma specimens.
- FPR was inhibited using short interfering (si) RNA in U-87 cells.
- Cell proliferation, tumor xenograft growth, and VEGF production were measured.
- Endogenous FPR agonist activity was assessed.
Main Results:
- FPR was selectively expressed in highly malignant glioblastoma cell lines and primary gliomas (grade IV and III).
- U-87 cells expressing FPR exhibited increased motility, proliferation, and VEGF production in response to the FPR agonist fMLF.
- FPR inhibition significantly reduced U-87 cell tumorigenicity in nude mice (P = .001).
- Necrotic glioblastoma cells released factors that activated FPR in U-87 cells.
Conclusions:
- FPR is expressed in aggressive human glioma cells and mediates glioblastoma cell motility, growth, and angiogenesis.
- FPR interacts with host-derived agonists to promote tumor progression.
- FPR represents a promising molecular target for novel antiglioma therapies.
