Pericytes Augment Glioblastoma Cell Resistance To Temozolomide Through Paracrine Signaling And Its Personalized Therapeutic Significance

Diffused glioma is the most common malignant brain tumor in adults and represents 75%of malignant brain tumor in adults.Among them,glioblastoma(GBM)is the most prevalent and invariably one.Even after complete surgical resection combined with standard chemotherapy and radiotherapy,the GBM patients have a lifetime of only 14.6 months.Temozolomide(TMZ)is the first-line chemoagent for the treatment of GBMs,which elongated 2.5 months of median survival time of GBM patients.However,some GBM cases do not respond to TMZ,which is called TMZ resistance.Unmethylated status of MGMT promoter was demonstrated as the most important mechanism of TMZ resistance.But MGMT depletion still cannot reverse the TMZ resistance phenotype completely,indicating other mechanisms independent of MGMT status existing in TMZ resistance of GBM.In-depth investigations of the causes and mechanisms of TMZ resistance and development of drugs that can improve TMZ sensitivity will bring new hope to glioma patients.Abundant vasculature is a key characteristic of GBM and provides essential environmental cues to support tumor propagation and progression.Glioma cells contact with components of tumor microenviroment(TME)thus sustaining their malignant behaviors.As critical elements of the vasculature,pericytes are auxiliary cells that wrap around the endothelial tubing of vessels.It has been well demonstrated that pericytes reciprocally interact with endothelial cells to regulate vascular functions in physiological contexts.The effect of pericytes on tumor cells is still under investigation.Previous study reported that about70%-80% pericytes in GBM xenografts were transdifferentiated from GSCs.Another study also demonstrated that nearly 50% of pericytes in GL261 xenografts came from GL261 glioma cells.Transdifferentiated pericytes were supposed to have malignant behavior like their progenitor cells,glioma stem cells(GSCs).Our previous study showed GBMs with higher pericyte coverage showed poor response to TMZ treatment,but the underline mechanism remained elusive.Herein,we interrogated the role of pericytes in regulating therapeutic efficacy of TMZ and investigated the underlying mechanisms.Besides,this research tried to make the preliminary evaluation of clinical application of the new molecular targeting therapeutic strategy to promote the sensitivity of TMZ.The main conclusions and significance of this study are listed as follows:1.Higher pericytes potent in glioma patients indicates inversely lower response to TMZ treatment.2.We succeeded isolated,identified and cultured glioma pericytes for the first time.3.We investigated the role of pericytes in mediating TMZ resistance in vitro and in vivo.4.C-C motif chemokine ligand 5(CCL5)was abundantly secreted by pericytes to mediate TMZ resistance.5.Silencing the CCL5-CCR5 signaling largely abrogates the tumor-supportive effects of pericytes and enhances the chemotherapeutic efficacy of TMZ because of enhanced DNA repair ability of GBM cells.6.Our preclinical data indicate that repurposing MVC as a CCL5-CCR5 targeting agent effectively improves the chemotherapeutic efficacy of TMZ against GBMs.Our study reveals the novel mechanism of the direct interaction of pericytes and GBM cells to enhance DNA repair and induce TMZ resistance through AKT/DNA-PK pathway in the paracrine dependent manner.We also raise a promising targeting approach to enhance TMZ sensitivity in glioma patients for further clinical applications.