The studies on the interstitial matrix and the long-term collaboration with Professor Kristofer Rubin at Uppsala University, Sweden has since the early 1990s been on acute inflammation and subsequently on experimental cancers, and in particular on the role of the hydrostatic pressure (Pif) and how a lowering of Pif will explain the initial and rapid edema formation in acute inflammation. In a series of collaborative studies it has been demonstrated that fiber networks
in the loose connective tissues are compressed by cellular tension mediated from the cells to the fibre networks via the beta1-integrin receptors. When this tension is released, the tissue expands due its content of glycosaminoglycans, in particular hyaluronan, and the Pif is lowered in turn pulling in water from the circulation to create a local edema. The tissue can be compacted again, with reversal of Pif, via the action of several chemokines and also prostaglandins, but now uses the alfaVbeta3-integrin to mediate cellular tension on to the fibre networks. The enhanced transcapillary fluid flux in the tumors during the lowering of Pif will raise the transport of cytostatic agents into the tumor, in turn slowing tumor growth compared to control.

A recent collaboration with Professor F.-R- Curry at University of California at Davis has focused on transcapillary exchange and development of methods for its measurement in genetically modified mice. The CCBIO projects in which Rolf Reed participates builds strongly
on the above collaborations and also with collaborations with Professors Linda Stuhr, Donald Gullberg and Marion Kusche Gullberg in the Matrix Biology group. The current focus has a particular focus on the role of integrins alpha11 and alfaVbeta3 in the
tumor stroma using:

a) tumor-fibroblast heterospheroids as a 3D model system to understand bidirectional communication between the tumor cells and fibroblasts. A long-term aim is to develop this system to a large scale in vitro system to screen for compounds targeting integrins/integrin signaling and with the potential to inhibit tumor growth and spreading.

b) transvascular exchange in acute inflammation and experimental cancers.

c) integrins alpha11 and alfaVbeta3 in the tumor stroma and how they modify tumor growth and preoperties.

d) the use of dynamic contrast enhanced magnetic resonance (DCEMRI) to study transcapillary exchange in genetically modified mice.

The long term goal of the research is to understand the tumor-stroma and its dynamic properties, and how this insight can be used to alter therapeutic principles of solid tumors.