Abstract
Background: Glioblastoma (GB) is the most representative form of primary malignant brain tumour. Several studies indicated a pleiotropic role of CXCL-8 in cancer due to its ability to modulate the tumour microenvironment, growth and aggressiveness of tumour cell. Previous studies indicated that CXCR1 (CXCL-8 receptor) induced activation of the PI3K/p-Akt pathway, a crucial event in the regulation of cytoskeleton rearrangement and cell migration. Methods: We used human GB primary cell culture and U-87MG cell line both exposed to a dual allosteric inhibitor of CXCR1/2 receptors. Cell migration assays associated with the analysis of protein involved in cell migration and cytoskeletal dynamics were performed. Findings: The data obtained indicate a specific effect of autocrine CXCL-8 signalling on GB cell invasiveness by the activation of pathways involved in cell migration and cytoskeletal dynamics,. The use of the inhibitor strongly affects cytoskeletal dynamic opposing to invasion. Interpretation: The data obtained support the concept that autocrine CXCL-8 signalling plays a key role in the activation of an aggressive phenotype in glioblastoma cells and U-87MG cell line. The strong effects of the allosteric inhibitor DF2755A in counteracting the key pathways involved in migration and invasion of GB, although not affect cell viability, suggest additional studies to assess the potential of a pharmacological approach targeting CXCR1/CXCR2 pathways to decrease migration and invasion of GB cells in the brain parenchyma, one of the principal mechanisms of recurrence. Funding Statement: This work was supported by the University of L'Aquila (RIA 2018). Declaration of Interests: Declarations of interests: Laura Brandolini and Marcello Allegretti are employees of Dompe Farmaceutici SpA, Italy. The company has interests in the development of CXCR1/2 allosteric modulator for the treatment of oncologic-related diseases. The other authors declare that they have no conflict of interest. Ethics Approval Statement: This study was ethically approved (Hospital Ethics Committee, n. 3729), and all patients voluntary signed informed consent.
Highlights
Glioblastoma (GB) is the most representative form of primary malignant brain tumour
The GB cellular models show different levels of CXCL8 and CXCR1/CXCR2 associated with autocrine CXCL8 signalling
CXCR1/CXCR2 expression and extracellular CXCL8 levels were analysed to evaluate the autocrine CXCL8 mediated signalling in GB
Summary
Glioblastoma (GB) is the most representative form of primary malignant brain tumour. The aggressive and invasive nature of GB and the refractoriness to the standard therapy lead to a high mortality rate of GB patients with a median overall survival of about 15-16 months [1,2,3,4,5,6]. Surgical resection of the tumour mass may fail to completely remove the infiltrative disease due to the risk of functional loss residual malignant cells may eventually contribute to tumour recurrence. Development of specific and effective therapies requires a deep understanding of the pathways governing the invasive behaviour of gliomas. The tremendous medical need has prompted plenty of research studies on the complex biological mechanisms accounting for glioma tumour cell invasiveness leading to the identification of several orchestrated signalling pathways implicated in www.aging-us.com this phenomenon [7]. There is strong evidence that several soluble factors contribute to the gliomagenesis and particular attention has been given to a potential role of chemokines in the regulation of tumour cell invasiveness due to the specific role of this protein family in the migration of circulating immune cells [8]
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