BBB seminar: Kristofer Rubin
Tumor stroma as a target to improve anti-cancer therapies
Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden
The stroma of both experimental and clinical carcinomas displays several pathological features distinguishing it from a normal connective tissue. Hallmarks include infiltrating myeloid cells, distorted blood vessels, hypoxia, low pH, pathologically high interstitial fluid pressure (IFP) and activated connective tissue cells that commonly produce a fibrotic extracellular matrix (ECM). These properties result in a disturbed physiology and e.g. poor uptake of anti-cancer drugs into the carcinoma. Tumor physiology, including properties of the stroma that determine transport phenomena in tumor tissues, therefore attracts an increasing interest. This interest is fueled by the need for improving existing chemotherapy.
We have established a mechanistic model for the control of the IFP in the connective tissues that embed all peripheral blood capillaries. IFP is one of the Starling forces that determine capillary-to-interstitium fluid transport. Acute inflammation in normal tissues lowers IFP and leads to edema formation. Our proposed model holds that connective tissue cells apply tensile forces on ECM-fibers that in turn restrain the under-hydrated ground substance from taking up fluid and swell. A decrease in cellular tension on the ECM fibers allows the ground substance to swell, i.e. form edema. During this process negative IFP values can be recorded if refilling of the tissue with fluid is inhibited. The tensile forces are mediated by integrins. Furthermore, they depend on cytoskeletal dynamics and can be pharmacologically modulated. Our data also show that fibroblast-mediated collagen gel contraction in vitro serves as a model for cellular control of IFP in vivo .
We and others have established a correlation between lowering IFP and uptake and efficacy of chemotherapeutic agents in carcinoma. Notably, using microdialysis, or magnetic resonance imaging, we have pro forma demonstrated that lowering of carcinoma IFP increased capillary-to-interstitium transport of low-molecular weight compounds including 5-fluorouracil (5FU) in experimental carcinoma. In addition, data from a model for anaplastic thyroid carcinoma (KAT-4) suggest that inflammatory processes and IFP are related functionally. We are engaged in elucidating the mechanisms by which IFP can be lowered in carcinoma. In the presentation special emphasis will be put on the importance of collagen network-architecture and carcinoma IFP.
Host: Rolf Kåre Reed <rolf.reed[@]biomed.uib.no>, Dept. of Biomedicine