Morphologic instability and cancer invasion.
OBJECTIVE
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.


METHODS
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 properly 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 vasculature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.
Cristini
Vittorio
V
Department of Biomedical Engineering, University of California, Irvine, California 92697-2715, USA. cristini@math.uci.edu
Frieboes
Hermann B
HB
Gatenby
Robert
R
Caserta
Sergio
S
Ferrari
Mauro
M
Sinek
John
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003198:Computer Simulation; D004058:Diffusion; D006801:Humans; D000860:Hypoxia; D008954:Models, Biological; D008956:Models, Chemical; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D010100:Oxygen