Neovascularization directed by CAVIN1/CCBE1/VEGFC confers TMZ-resistance in glioblastoma

  • Impact factors: 4.927
  • Publication: MOLECULES
  • Author:Yunhe Liu, Caixia Wang, Junzhe Wu, Luying Tan, Peng Gao, Sinuo Wu, Daohao Tang, Qianyun Wang, Cuizhu Wang, Pingya Li, Jinping Liu
  • DOI citation-doi:10.3390/molecules28041526
  • Date:2023-02-04

Acquisition of resistance to temozolomide (TMZ) poses a significant challenge in glioblastoma (GBM) therapy. Neovascularization, a pivotal process in tumorigenesis and development, remains poorly understood in its contribution to chemoresistance in GBMs. This study unveils aberrant vascular networks within TMZ-resistant (TMZ-R) GBM tissues and identifies the extracellular matrix (ECM) protein CCBE1 as a potential mediator. Through in vivo and in vitro experiments involving gain and loss of function assessments, we demonstrate that high expression of CCBE1 promotes hyper-angiogenesis and orchestrates partial endothelial-to-mesenchymal transition (EndMT) in human microvascular endothelial cells (HCMEC/d3) within GBM. This is likely driven by VEGFC/Rho signaling. Intriguingly, CCBE1 overexpression substantially fails to promote tumor growth, but endows resistance to GBM cells in a vascular endothelial cell-dependent manner. Mechanically, the constitutive phosphorylation of SP1 at Ser101 drives the upregulation of CCBE1 transcription in TMZ resistant tumors, and the excretion of CCBE1 depends on caveolae associated protein 1 (CAVIN1) binding and assembling. Tumor cells derived CCBE1 promotes VEGFC maturation, activates VEGFR2/VEGFR3/Rho signaling in vascular endothelial cells, and ultimately results in hyper-angiogenesis in TMZ-R tumors. Collectively, the current study uncovers the cellular and molecular basis of abnormal angiogenesis in a chemo resistant microenvironment, implying that curbing CCBE1 is key to reversing TMZ resistance.

Related Products

$447.00$569.00

$400.00$500.00

$400.00$500.00

$400.00$500.00

$400.00$500.00

$400.00$500.00

$400.00$500.00

$400.00$500.00

EK1392

$350.00$450.00

EK1242

$350.00$450.00

EK1C01

$350.00$450.00

EK1341

$350.00$450.00

EK1334

$350.00$450.00

EK2295

$350.00$450.00

EK224

$350.00$450.00

EK2100

$350.00$450.00

Hot products

Hot citation