Overcoming the extracellular matrix barrier to improve intratumoral spread and therapeutic potential of oncolytic virotherapy.

Genetically attenuated viruses are under development as selectively replicating antitumoral agents. However, the inability of adenoviral vectors to disseminate throughout a solid tumor mass remains a major obstacle in realizing the full potential of this therapeutic modality. Therefore, strategies aimed at increasing the anatomical distribution of a replicating virus within tumor tissues are highly desirable. Tumor extracellular matrix (ECM) is characterized by distorted blood vessels and activated connective tissue cells that produce a collagen-rich matrix. Elevation of interstitial fluid pressure acts as a physical barrier to the transport of macromolecules across the ECM. This review discusses advances in the development of oncolytic viruses that modulate the ECM to enhance viral spread within tumor tissues, several of which may also be applicable to non-replicating viral systems. In addition, the effect of apoptosis on viral spread throughout the tumor mass and 3-dimensional model systems for the study of viral spread are presented.