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[Cancer Research 60, 2497-2503, May 1, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

Role of Extracellular Matrix Assembly in Interstitial Transport in Solid Tumors1

Paolo A. Netti2, David A. Berk3, Melody A. Swartz4, Alan J. Grodzinsky and Rakesh K. Jain5

Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [P. A. N., D. A. B., M. A. S., R. K. J.], and Department of Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [A. J. G.]

The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.




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