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Assessing Tumor Microenvironment of Metastasis Doorway-Mediated Vascular Permeability Associated with Cancer Cell Dissemination using Intravital Imaging and Fixed Tissue Analysis
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Assessing Tumor Microenvironment of Metastasis Doorway-Mediated Vascular Permeability Associated with Cancer Cell Dissemination using Intravital Imaging and Fixed Tissue Analysis

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Increased survivin expression confers chemoresistance to tumor-associated endothelial cells

Jenilyn J Virrey1, Shengxi Guan, Wei Li

  • 1Departments of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Ave., HMR 315A, Los Angeles, CA 90033, USA.

The American Journal of Pathology
|July 5, 2008
PubMed

Insights

Survivin protein overexpression in brain tumor blood vessels causes chemotherapy resistance. Reducing survivin levels sensitizes tumor endothelial cells to cancer drugs, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Survivin, an inhibitor of apoptosis protein, is implicated in cancer drug resistance.
  • Tumor-associated endothelial cells (TuBECs) from gliomas exhibit chemoresistance, unlike normal brain endothelial cells (BECs).

Purpose of the Study:

  • To investigate the mechanism of chemoresistance in glioma-associated endothelial cells.
  • To determine the role of survivin in the chemoresistance of tumor vasculature.

Main Methods:

  • Constitutive survivin expression analysis in glioma vasculature versus normal brain vasculature.
  • Down-regulation of survivin in TuBECs using lentiviral siRNA or roscovitine.
  • Assessment of TuBEC sensitivity to chemotherapeutic agents (VP-16, paclitaxel, thapsigargin, temozolomide) after survivin reduction.
  • Forced expression of survivin in BECs to evaluate its protective effect.

Main Results:

  • Survivin is overexpressed in glioma vasculature but not in normal brain blood vessels.
  • Survivin down-regulation sensitized TuBECs to multiple chemotherapeutic agents, mediated by caspases 7 and 4.
  • Forced survivin expression in BECs conferred resistance to drug-induced cell death.

Conclusions:

  • Overexpression of survivin in tumor endothelial cells contributes to chemoresistance by protecting the vasculature.
  • Targeting survivin represents a potential strategy for chemosensitization and anti-vascular therapy in brain tumors.

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