Kristofer Rubin research group

Tumor stroma - a target for novel therapy

Loose connective tissue elements are present in all organs outside the central nervous system. They embed blood vessels and underlie mucosal surfaces and also constitute the stroma of carcinoma. During inflammatory processes leukocyte leave the blood vessels and enter the surrounding loose connective tissues. The composition of the interstitial matrix, i.e. the amount (concentration) and type of the fibrous scaffolding and ground substance, in concert with connective tissue cells determine the physical properties for convective and diffusive movement of molecules in the tissue. The loose connective tissue surrounding blood vessels was commonly thought of as a “passive” framework in the sense that its physical properties such as diffusivity, hydraulic conductivity, compliance and interstitial fluid pressure (IFP) remain fairly constant. This concept of a static and passive loose connective tissue has been challenged by recent research suggesting that IFP is “actively” controlled and therby also fluid content and possibly fluid fluxes through tissues.

Together with prof. Rolf Reed at Bergen University in Norway we have proposed a mechanism for control of IFP in vivo. Our proposed mechanistic 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 and 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 b1-integrins, in rat dermis the collagen-binding integrin a2b 1 is of particular importance. Furthermore, they depend on the cytoskeleton and can be pharmacologically modulated. Dermal IFP lowered after anaphylaxis can be normalized by instilments of platelet-derived growth factor (PDGF) BB or insulin. Our data suggest that whereas b1-integrins participate in fluid homeostasis, b3-integrins participate in PDGF BB-induced IFP-recovery after inflammation-induced lowering of dermal IFP.

One obstacle in the pharmaceutical treatment of carcinomas is the poor uptake of anti-cancer drugs into the tumor tissue. We have shown that the IFP in carcinoma reflects conditions that form a barrier for penetration of low-molecular compounds such as chemotherapy into the carcinoma tissue. Thus, lowering of carcinoma IFP by local treatment with prostaglandin E1 or by systemic treatment with inhibitors of the PDGF or TGF-b systems lower carcinoma IFP. This lowering of IFP is paralleled by increases up to three-fold on a concentration basis of the efficacy of conventional chemotherapy. We have spent a considerable effort in elucidating the mechanisms by which carcinoma IFP is controlled. Microarrays for gene expressions and other techniques such as immunohistochemistry, real-time PCR, imaging and cell analyses, all combined with physiological measurements in carcinoma grown in wild-type or transgenic animals have been adopted. We have a found a correlation with inflammatory processes and the architecture of the collagen network in the stroma.