title: VEGFR inhibitors upregulate CXCR4 in VEGF receptor-expressing glioblastoma in a TGFβR signaling-dependent manner.
abstract: The failure of standard treatment for patients diagnosed with glioblastoma (GBM) coupled with the highly vascularized nature of this solid tumor has led to the consideration of agents targeting VEGF or VEGFRs, as alternative therapeutic strategies for this disease. Despite modest achievements in survival obtained with such treatments, failure to maintain an enduring survival benefit and more invasive relapsing tumors are evident. Our study suggests a potential mechanism by which anti-VEGF/VEGFR therapies regulate the enhanced invasive phenotype through a pathway that involves TGFβR and CXCR4. VEGFR signaling inhibitors (Cediranib and Vandetanib) elevated the expression of CXCR4 in VEGFR-expressing GBM cell lines and tumors, and enhanced the in vitro migration of these lines toward CXCL12. The combination of VEGFR inhibitor and CXCR4 antagonist provided a greater survival benefit to tumor-bearing animals. The upregulation of CXCR4 by VEGFR inhibitors was dependent on TGFβ/TGFβR, but not HGF/MET, signaling activity, suggesting a mechanism of crosstalk among VEGF/VEGFR, TGFβ/TGFβR, and CXCL12/CXCR4 pathways in the malignant phenotype of recurrent tumors after anti-VEGF/VEGFR therapies. Thus, the combination of VEGFR, CXCR4, and TGFβR inhibitors could provide an alternative strategy to halt GBM progression.
authors: Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Kien
authors: K
authors: Pham
authors: Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Defang
authors: D
authors: Luo
authors: Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Dietmar W
authors: DW
authors: Siemann
authors: Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Brian K
authors: BK
authors: Law
authors: Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Brent A
authors: BA
authors: Reynolds
authors: The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA 98122, USA.
authors: Parvinder
authors: P
authors: Hothi
authors: The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA 98122, USA.
authors: Gregory
authors: G
authors: Foltz
authors: Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: jharriso@ufl.edu.
authors: Jeffrey K
authors: JK
authors: Harrison
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000080027:Cyclams; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020239:Receptor Cross-Talk / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D053645:Interleukin-2 Receptor alpha Subunit; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019718:Receptors, CXCR4; D018125:Receptors, Transforming Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; C527276:CXCR4 protein, human; C508018:Il2ra protein, mouse; C500926:cediranib; D007211:Indoles; C088327:plerixafor; C452423:vandetanib
keywords: Anti-angiogenic therapy; CXCR4; GBM; MET; TGFβR; VEGFR