Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci U S A 2008 Aug 12;105(32):11305-10
Date
08/08/2008Pubmed ID
18685096Pubmed Central ID
PMC2516246DOI
10.1073/pnas.0800835105Scopus ID
2-s2.0-49649125325 (requires institutional sign-in at Scopus site) 175 CitationsAbstract
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.
Author List
Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DEAuthor
Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAdenocarcinoma
Amides
Animals
Cell Shape
Cytoskeleton
Elasticity
Endothelial Cells
Enzyme Inhibitors
Extracellular Matrix
G-Protein-Coupled Receptor Kinase 1
Male
Mechanotransduction, Cellular
Mice
Mice, Transgenic
Neovascularization, Pathologic
Prostatic Neoplasms
Pyridines
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
rho GTP-Binding Proteins
