Morphologic Instability and Cancer Invasion

• Published in: Clinical cancer research Vol. 11; no. 19; pp. 6772 - 6779
• Main Authors: CRISTINI, Vittorio, FRIEBOES, Hermann B, GATENBY, Robert, CASERTA, Sergio, FERRARI, Mauro, SINEK, John
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-2005
• Subjects: antiangiogenic therapy; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Adhesion; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Proliferation; Computer Simulation; Diffusion; Dissemination; Humans; Hypoxia; Medical sciences; Models, Biological; Models, Chemical; Necrosis; Neoplasm Invasiveness; Neoplasms - pathology; Neovascularization, Pathologic; Oxygen - metabolism; Time Factors; Tumor cell; tumor invasion; tumor morphology instability; Tumors; Morphological variation; Computer simulation; Dissemination; Instability; Malignant tumor; Antiangiogenic agent; In vitro; Invasion; Molecular microenvironment
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0852

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 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.