Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 32, Pages 11305-11310Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0800835105
Keywords
capillary; contractility; elasticity; GTPase; mechanotransduction
Categories
Funding
- NCI NIH HHS [CA-37392, R37 CA037392, R01 CA177875, P01 CA045548, R01 CA037392, CA-58833, R56 CA037392, CA-45548, L30 CA117002] Funding Source: Medline
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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.
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