Role of extracellular matrix assembly in interstitial transport in solid tumors.

TLDR

The extracellular matrix may contribute to drug resistance in solid tumors by impeding therapeutic agent penetration. Interstitial IgG diffusion was quantified in situ using fluorescence redistribution after photobleaching, while tissue elastic modulus and hydraulic conductivity were assessed by confined compression of excised tumor samples. We found that interstitial resistance to IgG correlates with tumor stiffness and collagen content, that collagenase treatment markedly increases IgG diffusion, and that collagen–proteoglycan interactions represent a target to enhance macromolecule delivery and screen for therapeutic resistance.

Abstract

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.