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Normalizing tumor vessels to improve cancer therapy
Date:8/25/2008

ifferent approach, focusing on the role of mechanical forces on tumor blood vessels, which had previously been ignored. Past studies by Ingber and colleagues have shown that a capillary cell's sensitivity to soluble angiogenic factors like VEGFand subsequent blood vessel formationare determined by the mechanical balance between the cell's internal state of tension or contraction, and that of the surrounding support structure, or matrix, to which the cell adheres. These forces guide normal vascular pattern formation. Because tumor vessels are malformed, Ghosh wondered whether tumor capillary cells have lost the normal cells' ability to sense and respond to changes in matrix stiffness and distortion.

To address this question, the researchers studied capillary cells isolated from mice prostate tumors, provided by Andrew Dudley, PhD, in the lab of Michael Klagsbrun, PhD, in the Vascular Biology Program, and exposed them to cyclic mechanical stressmimicking the pulsatile nature of blood flow and matrix distortion resulting from rhythmic heart beats. They found that normal capillary cells aligned themselves uniformly perpendicular to the force direction, but most of the tumor capillary cells failed to reorient, says Ghosh. These cells were "all over the place," and due to this lack of alignment, gaps appeared between neighboring cells, which may explain the increased vessel permeability.

Ghosh and colleagues also found that tumor capillary cells sense and respond to matrix rigidity differently than normal cells. When placed on a stiff surface, mimicking the tumor matrix, the cells tended to keep spreading even after normal capillary cells stopped doing so. Because of these differences in "mechanosensing," the tumor capillary cells were able to form capillaries even when cell densities were very low, while normal cells failed to do so. At higher cell densities, normal cells formed nice capillaries, whereas the tumor cells balled up into tangled clumps,
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Contact: Bess Andrews
Elizabeth.Andrews@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert

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