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Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

ABSTRACT: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), illustrating that GBM cells may use plasticity in concert with vascularization leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation, however, remains unclear. Here, we show that treatment with temozolomide (TMZ) chemotherapy induces time-dependent expression of markers for glioma stem cells (GSCs) and immature and mature ECs. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed increased expression of GSC and EC markers after TMZ treatment. Ex vivo FACS analysis showed the presence of immature and mature EC populations. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.

SUBMITTER: Baisiwala S

PROVIDER: S-EPMC6604352 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

Baisiwala Shivani S Auffinger Brenda B Caragher Seamus P SP Shireman Jack M JM Ahsan Riasat R Lee Gina G Hasan Tanwir T Park Cheol C Saathoff Miranda R MR Christensen Anne C AC Ahmed Atique U AU

Stem cells international 20190618

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents. Recent resear ...[more]

PMID: 31316566

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Project description:BackgroundGlioblastoma multiforme (GBM) is one of the lethal malignant tumors of the central nervous system. Despite advances made in understanding this complex disease, little has been achieved in improving clinical efficacy towards it. Factors such as chemokines play important role in shaping the tumor microenvironment which in turn plays a significant role in deciding course of tumor progression. In this study, we investigated the role of chemokine IL-8 in glioblastoma progression with particular emphasis on immunomodulation, cellular proliferation, invasion and vascular mimicry.MethodsRole of IL-8 in GBM immunology was determined by correlating the expression of IL-8 by immunohistochemistry with other immune cell markers such as CD3 and CD68. Effect of high IL-8 expression on overall survival, the difference in expression level between different GBM subgroups and anatomic structures were analyzed using other databases. Two GBM cell lines -U-87MG and LN-18 were used to study the impact of targeting IL-8-CXCR1/2 signalling using neutralizing antibodies and pharmacological antagonist. Reverse transcriptase-polymerase chain reaction and immunocytochemistry were used to determine the expression of these axes. Impact on cell viability and proliferation was assessed by MTT, proliferation marker-ki-67 and clonogenic survival assays. Multicellular tumor spheroids generated from GBM cell lines were used to study invasion in matrigel.ResultsWeak Positive correlation was observed between IL-8 and CD3 as well as between IL-8 and CD68. High IL-8 expression in GBM patients was found to be associated with dismal survival. No significant difference in IL-8 expression between different molecular subgroups of GBM was observed. In vitro targeting of IL-8-CXCR1/2 signalling displayed a significant reduction in cell viability and proliferation, and spheroid invasion. Furthermore, the presence of CD34-/CXCR1+ vessels in GBM tissues showed the involvement of IL-8/CXCR1 in vascular mimicry structure formation.ConclusionThese results suggest a direct involvement of IL-8-CXCR1/2 axes in GBM progression by promoting both cell proliferation and invasion and indirectly by promoting neovascularization in the form of vascular mimicry.

Dataset Information

Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

Publications

Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

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