Kristofer Rubin, PhD, professor

Members of the group

• Tomas Friman,MSc, PhD student
• Renata Gutsafsson, PhD, postdoctoral fellow
• Sebastian Kalamajski, PhD, postdoctoral fellow
• Lena Persson, PhD student (part time)
• Tijs van Wieringen, graduate student
  

Publications 2004-2008

LOOSE CONNECTIVE TISSUES - TARGETS FOR NOVEL THERAPIES IN CANCER AND INFECTIOUS DISEASES

Kristofer Rubin and Cecilia Rydén 

Loose connective tissues embed peripheral blood vessels and underlie epithelial sheets. Inflammatory processes, cancer invasion and infections occur in and are dependent on this compartment. Loose connective tissue structures are intrinsic to all organs outside the central nervous system. They are important not only as structural organ compartments but also actively maintain fluid homeostasis and filtration, as well as fulfilling important functions in innate immunity. The cellular and molecular mechanisms that control function and regeneration of loose connective tissue are less well understood. Our research aims at increasing the understanding of such mechanisms during homeostasis and pathologic conditions such as cancer growth, infection and chronic inflammation.

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TUMOR STROMA AS A TARGET FOR NOVEL CANCER THERAPY

Kristofer Rubin

We have established a mechanistic model for the control of capillary-to-interstitium transport of fluid. Interstitial fluid pressure (IFP) is one of the Starling forces that determine fluid transport in the connective tissues, which embed all peripheral blood capillaries. 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, these forces 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 propose that modulation of IFP is part of the innate immune response and is relevant for edema formation. Edema formation is one of the classic signs of inflammation induced by e.g. invading bacteria. The pathophysiologic relevance of edema formation is most likely to increase drainage from the tissue, as well as to facilitate for phagocytes and soluble anti-microbial proteins to reach the infectious foci.

The stroma of both experimental and clinical carcinomas displays several pathologic features distinguishing it from a normal connective tissue but resembling chronically inflamed tissues. Characteristics include infiltrating myeloid cells, distorted blood vessels, hypoxia, low pH, pathologically high IFP and activated connective tissue cells that commonly produce a fibrotic ECM. These properties result in a disturbed physiology and e.g. poor uptake of anti-cancer drugs into the carcinoma. Our interest in tumor stroma physiology is fueled by the need for improvements of existing chemotherapy.

We have shown that lowering of IFP in experimental carinoma increases uptake and efficacy of chemotherapeutic agents. 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, our data suggest that inflammatory processes and IFP are related functionally. We are engaged in elucidating the mechanisms by which IFP can be lowered in experimental carcinoma. Furthermore, our research aims at devising clinically relevant methods to improve efficacy of existing chemotherapy for the treatment of carcinoma.

INFECTIONS IN CONNECTIVE TISSUE
Cecilia Rydén

Publication list (Pdf-file)

Agencies supporting the work.

The Swedish Cancer Society, the Swedish Science Council, the Swedish Medical Association, The Children's Cancer Foundation of Sweden and King Gustaf V:s 80-year foundation.