Overexpression of protease-activated receptor type 1 (PAR-1) in glioblastoma multiforme WHO IV cells and blood vessels revealed by NCAM-assisted glioblastoma border labeling

Abstract

Glioblastomas are neuroepithelial tumors with lost cellular differentiation and tenfold increased growth rates compared to low-grade gliomas. Despite of very aggressive treatment options based on surgery, irradiation, and chemotherapy, the prognosis of affected patients has remained poor and showed only slight improvements during the last 30 years. Research on glioblastoma border zone was hindered by the tumor's intense invasion into the brain parenchyma and the lack of suitable tumor cell markers. Nevertheless, the compact tumor mass and tumor invasion zone are composed of distinct cell types that need to be distinguished from each other to be addressed selectively. As the isoform 140 of the neural cell adhesion molecule (NCAM-140) was recently demonstrated to be lost in human gliomas with rising WHO grade, human multiform glioblastomas were characterized as a NCAM-140 negative entity displaying three main distinct invasion patterns. Evaluation of putative therapy targets within the tumor tissue and tumor invasion zone has been made possible through NCAM-140 negativity. In the present study, brain tissue controls and human glioblastoma samples with compact tumor mass and invasion areas were analyzed for their vascularization at the tumor border and the expression of thrombin receptor protease-activated receptor type 1 (PAR-1) within tumor tissue and vascular vessel walls. Use of NCAM-140 enabled the identification of the tumor invasion zone and its experimental investigation. Tissue vascularization was found to be significantly increased in the compact tumor mass of glioblastomas compared to their invasion zone and tumor-free controls with a significantly high and specific overexpression of PAR-1 within tumor cells and within tumor blood vessels depending upon the tumor area. This suggests thereby a functional role of the thrombin receptor PAR-1 in glioma cell malignancy and glioblastoma neoangiogenesis.

Dabigatran antagonizes growth, cell‐cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines

“…In agreement with previous data, flow cytometry with PAR‐1‐specific antibody confirmed high levels of PAR‐1 surface expression in glioblastoma and breast cancer cells (not shown) . We then measured the proliferation of tumor cells in the presence of thrombin by means of a colorimetric assay assessing the direct correlation between metabolic activity and cell number.…”

Construction and analysis of lncRNA-lncRNA synergistic networks to reveal clinically relevant lncRNAs in cancer

“…Evidences also shows that activation of PAR1 (F2R) induces changes in cell morphology associated with increased cell motility and plays a critical role in cancer cell invasion and metastasis [ 49 ]. In addition, DUSP3 has been implicated in human cancer, though it has been alternatively described as having tumor suppressive and oncogenic properties [ 50 ].…”

PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

“…Furthermore, the anti-angiogenic effects of PAR1 antagonism, and the disruption of the tumor stem cell microenvironment resulting from abrogating PAR1-dependent interactions of the microvasculature with glioma progenitor cells, 22 may serve to further potentiate the antineoplastic effects of PAR1 inhibition. That said, the attractiveness of PAR1 as a therapeutic target is tempered by its expression by normal astrocytic and neuronal populations alike, 52 as well as by resident neural stem cells.…”

“…14–17 Among neuroectodermal cancers, PAR1 has been recently proposed as a highly expressed therapeutic target in melanoma. 18,19 PAR-1 is similarly overexpressed by GBM, 13,20–22 and its level of expression has been reported to correlate with tumor grade, such that higher levels of PAR1 predict low Karnovsky performance scores and poor prognosis. 20,23 …”