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Isolation and Culture Expansion of Tumor-specific Endothelial Cells
10:15

Isolation and Culture Expansion of Tumor-specific Endothelial Cells

Published on: October 14, 2015

Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro

Kaustabh Ghosh1, Charles K Thodeti, Andrew C Dudley

  • 1Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital and Harvard Medical School, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|August 8, 2008
PubMed

Insights

Tumor endothelial cells form abnormal blood vessels due to impaired sensing of mechanical cues from the extracellular matrix. Inhibiting Rho-associated kinase (ROCK) normalizes these responses, suggesting a new therapeutic target for cancer microvasculature.

Area of Science:

  • Biomedical Engineering
  • Cell Biology
  • Cancer Research

Background:

  • Tumor blood vessels are structurally and functionally abnormal, hindering anti-cancer agent delivery.
  • While anti-angiogenic factors like VEGF are targeted, mechanical forces from the extracellular matrix also influence endothelial cell behavior.

Purpose of the Study:

  • To investigate if tumor capillary endothelial (CE) cells' abnormal vessel formation stems from a diminished ability to sense and respond to physical cues.
  • To explore the role of Rho-mediated signaling in tumor CE cell mechanosensing and aberrant behavior.

Main Methods:

  • Compared tumor-derived CE cells with normal CE cells regarding responses to mechanical stimuli like cyclic strain and ECM elasticity.
  • Assessed actin cytoskeleton reorientation, cell shape, traction force, and in vitro tubular network formation.
  • Investigated the role of the Rho/ROCK pathway by measuring its activity and using a ROCK inhibitor (Y27632).

Main Results:

  • Tumor CE cells showed impaired actin cytoskeleton reorientation under strain and distinct shape sensitivity to ECM elasticity compared to normal CE cells.
  • Tumor CE cells exhibited increased traction force and enhanced ability to retract ECM and form tubular networks in vitro.
  • These abnormal behaviors correlated with high baseline activity of the small GTPase Rho and Rho-associated kinase (ROCK).
  • Inhibition of ROCK with Y27632 normalized tumor CE cell responses to mechanical strain and tubular network formation.

Conclusions:

  • Tumor CE cells possess an abnormal ability to sense and respond to mechanical cues from the extracellular matrix, contributing to aberrant tumor vasculature.
  • Dysregulated Rho-mediated signaling and tension are key factors in tumor CE cell mechanotransduction defects.
  • Targeting Rho-mediated mechanical sensing presents a potential strategy for normalizing tumor vasculature and improving anti-cancer therapy efficacy.

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