This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cristini, V. Articles by Sinek, J. Search for Related Content PubMed PubMed Citation Articles by Cristini, V. Articles by Sinek, J.

Morphologic Instability and Cancer Invasion

Authors' Affiliations: Departments of ¹ Biomedical Engineering and ² Mathematics, University of California, Irvine, California; Departments of ³ Radiology and ⁴ Applied Mathematics, University of Arizona, Tucson, Arizona; ⁵ Department of Chemical Engineering, University of Naples "Federico II," Naples, Italy; ⁶ Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio; and ⁷ National Cancer Institute, Bethesda, Maryland

Requests for reprints: Vittorio Cristini, Department of Biomedical Engineering, REC 204, University of California, Irvine, CA 92697-2715. Phone: 949-824-9132; Fax: 949-824-1727; E-mail: cristini{at}math.uci.edu.

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.

This article has been cited by other articles:

				A. M. Stein, T. Demuth, D. Mobley, M. Berens, and L. M. Sander A Mathematical Model of Glioblastoma Tumor Spheroid Invasion in a Three-Dimensional In Vitro Experiment Biophys. J., January 1, 2007; 92(1): 356 - 365. [Abstract] [Full Text] [PDF]

				Z. F. Yang, R. T.P. Poon, Y. Liu, C. K. Lau, D. W. Ho, K. H. Tam, C. T. Lam, and S. T. Fan High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis. Mol. Cancer Ther., September 1, 2006; 5(9): 2261 - 2270. [Abstract] [Full Text] [PDF]

				H. B. Frieboes, X. Zheng, C.-H. Sun, B. Tromberg, R. Gatenby, and V. Cristini An Integrated Computational/Experimental Model of Tumor Invasion Cancer Res., February 1, 2006; 66(3): 1597 - 1604. [Abstract] [Full Text] [PDF]