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

Abstract

Tumor blood vessels exhibit abnormal structure and function that cause disturbed blood flow and high interstitial pressure, which impair delivery of anti-cancer agents. Past efforts to normalize the tumor vasculature have focused on inhibition of soluble angiogenic factors, such as VEGF; however, capillary endothelial (CE) cell growth and differentiation during angiogenesis are also influenced by mechanical forces conveyed by the extracellular matrix (ECM). Here, we explored the possibility that tumor CE cells form abnormal vessels because they lose their ability to sense and respond to these physical cues. These studies reveal that, in contrast to normal CE cells, tumor-derived CE cells fail to reorient their actin cytoskeleton when exposed to uniaxial cyclic strain, exhibit distinct shape sensitivity to variations in ECM elasticity, exert greater traction force, and display an enhanced ability to retract flexible ECM substrates and reorganize into tubular networks in vitro. These behaviors correlate with a constitutively high level of baseline activity of the small GTPase Rho and its downstream effector, Rho-associated kinase (ROCK). Moreover, decreasing Rho-mediated tension by using the ROCK inhibitor, Y27632, can reprogram the tumor CE cells so that they normalize their reorientation response to uniaxial cyclic strain and their ability to form tubular networks on ECM gels. Abnormal Rho-mediated sensing of mechanical cues in the tumor microenvironment may therefore contribute to the aberrant behaviors of tumor CE cells that result in the development of structural abnormalities in the cancer microvasculature.

• Authors: Kaustabh Ghosh, Charles K Thodeti, Andrew C Dudley, Akiko Mammoto, Michael Klagsbrun, Donald E Ingber
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 32 Pg. 11305-10 (Aug 12 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18685096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Actins
• Amides
• Enzyme Inhibitors
• Pyridines
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Y 27632
• G-Protein-Coupled Receptor Kinase 1
• Grk1 protein, mouse
• rho GTP-Binding Proteins

Topics

• Actins (metabolism)
• Adenocarcinoma (blood supply, metabolism, pathology)
• Amides (pharmacology)
• Animals
• Cell Shape
• Cytoskeleton (metabolism, pathology)
• Elasticity
• Endothelial Cells (metabolism, pathology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Matrix (metabolism, pathology)
• G-Protein-Coupled Receptor Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Mechanotransduction, Cellular
• Mice
• Mice, Transgenic
• Neovascularization, Pathologic (metabolism, pathology)
• Prostatic Neoplasms (blood supply, metabolism, pathology)
• Pyridines (pharmacology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (biosynthesis)
• rho GTP-Binding Proteins (metabolism)