Highly malignant human glioblastoma and anaplastic astrocytoma specimens express a formylpeptide receptor FPR, which is normally expressed in myeloid cells and results in their chemotaxis and activation induced by bacterial peptides. Screening of human glioma cell lines revealed that FPR was expressed only in more highly malignant glioma cell lines. FPR expressed in glioblastoma cell lines mediates tumor cell migration, proliferation and production of angiogenic factors, vascular endothelial growth factor (VEGF) and IL-8 (CXCL8), in response to agonist molecules released by necrotic tumor cells. Stimulation of FPR in glioblastoma cells also activates the receptor for epidermal growth factor (EGFR) by a signal transduction cascade that increases the phosphorylation of a selected tyrosine residue in the intracellular domain of EGFR. This transactivation of EGFR by FPR accounts for part of the capacity of FPR to mediate tumor cell migration and activation. Depletion of either FPR or EGFR in tumor cells by small interference (si) RNA each reduced the capacity of the tumor cells to form actively growing tumors in nude mice. However, depletion of both receptors completely abolishes the tumorigenicity of glioblastoma cells. Mechanistic studies of the regulation of aberrantly expressed FPR in glioblastoma cells revealed increased methylation in the promoter region of p53 gene, which reduced the capacity of p53 to repress FPR in tumor cells. This was reversed by reduction of methylation in p53 gene promoter and differentiation of glioblastoma cells into lesser malignant phenotype. Thus, FPR plays an important role in promoting glioblastoma progression and is a molecular targets for the design of novel anti-glioblastoma therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010015-17
Application #
8552635
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$489,899
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Liu, Qiang; Cui, Xiang; Yu, Xi et al. (2017) Cripto-1 acts as a functional marker of cancer stem-like cells and predicts prognosis of the patients in esophageal squamous cell carcinoma. Mol Cancer 16:81
Lin, Shuye; Lin, Bonan; Wang, Xiaoyue et al. (2017) Silencing of ATP4B of ATPase H(+)/K(+) Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells. Oncol Res 25:317-329
Hou, Xi-Lu; Ji, Cheng-Dong; Tang, Jun et al. (2017) FPR2 promotes invasion and metastasis of gastric cancer cells and predicts the prognosis of patients. Sci Rep 7:3153
De Buck, Mieke; Gouwy, Mieke; Wang, Ji Ming et al. (2016) The cytokine-serum amyloid A-chemokine network. Cytokine Growth Factor Rev 30:55-69
Li, Liangzhu; Chen, Keqiang; Xiang, Yi et al. (2016) New development in studies of formyl-peptide receptors: critical roles in host defense. J Leukoc Biol 99:425-35
Yoshimura, Teizo; Imamichi, Tomozumi; Weiss, Jonathan M et al. (2016) Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage Colony-Stimulating Factor by Breast Cancer Cells. Front Immunol 7:2
Zhang, Liang; Wang, Huanyu; Yang, Tianshu et al. (2016) Formylpeptide receptor 1 mediates the tumorigenicity of human hepatocellular carcinoma cells. Oncoimmunology 5:e1078055
Guo, Zheng-Jun; Yang, Lang; Qian, Feng et al. (2016) Transcription factor RUNX2 up-regulates chemokine receptor CXCR4 to promote invasive and metastatic potentials of human gastric cancer. Oncotarget 7:20999-1012
Liu, Jia-Jia; Liu, Jun-Yan; Chen, Jun et al. (2016) Scinderin promotes the invasion and metastasis of gastric cancer cells and predicts the outcome of patients. Cancer Lett 376:110-7
Chen, Keqiang; Wang, Ji Ming; Yuan, Ruoxi et al. (2016) Tissue-resident dendritic cells and diseases involving dendritic cell malfunction. Int Immunopharmacol 34:1-15

Showing the most recent 10 out of 31 publications