TY - JOUR
T1 - Morphologic instability and cancer invasion
AU - Cristini, Vittorio
AU - Frieboes, Hermann B.
AU - Gatenby, Robert
AU - Caserta, Sergio
AU - Ferrari, Mauro
AU - Sinek, John
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/10/1
Y1 - 2005/10/1
N2 - Purpose: A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue. Experimental Design: We used computer simulations and in vitro experiments. Results: We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A property working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks. Conclusions: We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vascutature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.
AB - Purpose: A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue. Experimental Design: We used computer simulations and in vitro experiments. Results: We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A property working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks. Conclusions: We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vascutature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.
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U2 - 10.1158/1078-0432.CCR-05-0852
DO - 10.1158/1078-0432.CCR-05-0852
M3 - Article
C2 - 16203763
AN - SCOPUS:26444591026
SN - 1078-0432
VL - 11
SP - 6772
EP - 6779
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19 I
ER -