Collagen of the extracellular matrix. Functional and structural studies.

The cancer microenvironment has been attracting increasing attention as the realization of its importance for both disease treatment and malignant progression. Here the aim was to elucidate some of the effects and mechanisms of the tumor microenvironment related to the extracellular matrix (ECM). We hypothesized that collagen fibril assembly is an instrumental component in the formation of the barriers for transport of small molecules into carcinoma that have been seen in the treatment of carcinoma. To investigate this hypothesis we have utilized human xenograft and syngeneic generated tumors in mice, cellular and biochemical analyses. We found that fluid flow through carcinoma interstitium can be increased through STI571 treatment, and that this flow corresponds with a decreasing collagen fibril diameter. Additionally STI571 was found to increase blood flow and tumor oxygenation in a manner that correlates to matrix composition. Collagen fibril diameter was decreased via inhibition of the TGF-β activating integrin αvβ6 which corresponded to a clear trend toward a decreased interstitial fluid pressure, in all but the most fibrotic tumors. This illustrates the diversity of actable agents involved in stromal change. It points to a central role of collagen in the maintenance and regulation of fluid and solute exchange in tumors. Based on these results it may be possible to beneficially augment tumor treatment by altering one or more of the regulatory elements in the stroma of carcinoma.