A Cancer Gene Therapy Approach that Targets Tumor-associated Hyaluronan

The extracellular matrix glycosaminoglycan hyaluronan plays a key role in the development and pathogenesis of malignant disease. Reflecting its functional importance, the molecule is expressed at greatly elevated levels within many solid tumors. Although little explored, differences in the level of hyaluronan present in normal and malignant tissues could potentially be exploited to more effectively target gene therapy to tumor sites in vivo. As a first step toward this goal, we describe here a family of chimeric proteins in which the extracellular ligand-binding domain of the hyaluronan receptor CD44 is fused in-frame to the cytoplasmic “death domain” of the pro-apoptotic protein Fas. Although these chimeric proteins can be stably expressed on the surface of transduced tumor cells in the absence of hyaluronan, upon interaction with the ligand, apoptosis is rapidly induced. Both exogenous and endogenous tumor- produced hyaluronan can function as triggers, dramatically reducing clonogenic potential. Together, these studies help validate a broadly applicable gene therapy approach in which the presence of particular multivalent ligands within the tumor microenvironment can be exploited for therapeutic gain.