Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagen and Cancer Cells, and Implications for Cancer Therapy

• DOI: 10.1016/j.neo.2016.10.001
• Publication Date: 2016-11-22T12:19:04Z
• Authors: Chrysovalantis Vo...; Christiana Polydorou; Panagiotis Papage...; Vasiliki Gkretsi; Triantafyllos Sty...
• Keywords: collagen; 0301 basic medicine; Mice; Neoplasms; hyaluronic acid; Tumor Cells, Cultured; Edema; animal; Hyaluronic Acid; cancer cell; multicellular spheroid; Cultured; Tumor; Tumor Cells; Extracellular Matrix; 3. Good health; female; spheroid cell; priority journal; Heterografts; Female; Collagen; Original article; in vitro study; extracellular matrix; hyaluronidase; drug repositioning; cancer growth; Article; animal tissue; Cell Line; histology; in vivo study; 03 medical and health sciences; Osmotic Pressure; Cell Line, Tumor; Spheroids, Cellular; tumor microenvironment; Animals; Humans; controlled study; human; Collagenases; xenograft; mouse; blood vessel function; nonhuman; Animal; practice guideline; human cell; animal model; disease model; mechanical stress; tumor cell line; tumor cell culture; collagenase; Disease Models, Animal; drug effects; osmotic pressure; Disease Models; solid tumor; pathology; Cellular; pirfenidone; Spheroids; metabolism; edema; mathematical model; neoplasm

Despite the important role that mechanical forces play in tumor growth and therapy, contribution of swelling to mechanopathology remains unexplored. Tumors rich hyaluronan exhibit a highly negative fixed charge density. Repulsive among these charges as well cancer cells due regulation intracellular tonicity can cause development stress might compress blood vessels, compromising perfusion drug delivery. Here, we designed an experimental strategy, using four orthotopic models, measure related extracellular matrix components, collagen, perfusion. Subsequently, interventions were performed matrix-modifying enzymes (hyaluronidase collagenase) by repurposing pirfenidone, approved antifibrotic drug. Finally, vitro experiments on cell spheroids identify their tissue swelling. Swelling was measured range 16 75 mm Hg, high enough vessel collapse. Interestingly, while depletion decreased swelling, collagen had opposite effect, whereas negligible. Furthermore, histological analysis revealed same linear correlation between ratio content when data from all models combined. Our further inverse relation suggesting reduction decompresses vessels. These results provide guidelines for emerging therapeutic strategies target microenvironment alleviate intratumoral stresses improve functionality