Role of extracellular matrix assembly in interstitial transport in solid tumors

The extracellular matrix (ECM) may contribute to the drug resistance of a s olid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule. (IGG) motion in f our tumor types and found an unexpected correspondence between transport re sistance and the mechanical stiffness. The interstitial diffusion coefficie nt of IGG was measured in situ by fluorescence redistribution after photobl eaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an ex isting paradigm, these functional properties are correlated with total tiss ue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenese treatme nt of the more penetration-resistant tumors significantly increased the IGG interstitial diffusion rate. We conclude that collagen influences the tiss ue resistance to macromolecule transport, possibly by binding and stabilizi ng the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based th erapy. Moreover, collagen and collagen-proteoglycans bonds are identified a s potential targets of treatment to improve macromolecule delivery.