Morphologic Instability and Cancer Invasion

Purpose: A solidt umor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen andce ll nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia andac idosis, and may result in spatially heterogeneous cell proliferation and migration.Here,we formulate the hypothesis that through thesemechanisms,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 usedc omputer simulations and in vitro experiments. Results:We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen andn utrient 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 andn utrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promotemorphologic instability, leading to invasive patterns even under conditions inwhich 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 inmultiple clinical trials.We propose that antiangiogenic strategies will be more consistently successful when aimedat ‘‘normalizing’’ the vasculature andw hen combinedw ith therapies that increase cell adhesion so that morphologic instability is suppresseda nd compact, noninvasive tumormorphologies are enforced.