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Centre for Cancer Biomarkers CCBIO

Transcapillary Exchange

The Rolf Reed Group is working on the role of the collagen matrix as a determinant for the biophysical properties of tumors. The ongoing studies on experimental cancers originate from a long-term collaboration with Professor Kristofer Rubin at Lund University, Sweden and more recently with Professor Donald Gullberg at UiB.

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Rolf Reed in his office.
Photo:
Ingvild Melien

The studies have demonstrated that the connective tissue in general, including experimental tumors, can modify the interstitial fluid pressure via an interaction between cellular tension in the fiber networks in the tissue and the cellular collagen binding integrin receptors. The raised interstitial pressure and ”interstitial hypertension” constitutes a functional barrier towards the movement of substances across the tumor microcirculation.

The long term goal is to provide insight into how the interstitial hypertension can be modified by the tumor microenvironment and potentially give insight towards potential means by which it can be attenuated and thereby possibly pave the way for improved therapy.

The group’s projects

The specific focus for ongoing studies is on the role of the collagen binding integrin α11 and αVβ3 since the latter is taking over for the former when integrin α11 is lacking. It has been demonstrated that carcinomas from integrin β(3)-deficient mice have denser and coarser collagen network compared to controls and with elevated interstitial pressure in experimental carcinomas. The studies are extended to more tumor types and also to study the effect on tumor stroma when the stromal cells are lacking integrin α11. An extension of the above studies involves collaboration with Professors Gullberg and Akslen in CCBIO to investigate integrin α11 in human cancers. This collaboration now also includes Professors Trine Bjøro and David Warren at the University of Oslo and testing of antibodies towards the human integrin α11 with the specific aim to investigate whether it can serve as a biomarker in human cancers. 

Furthermore, the CCBIO projects involve studies with Professors Donald Gullberg and Marion Kusche Gullberg in the Matrix Biology Group using tumor-fibroblast heterospheroids as a 3D model system to understand communication between the tumor cells and fibroblasts. Regarding the role of integrins α11 and αVβ3 in the tumor stroma, a long-term goal is to develop a vitro system to screen for compounds targeting integrins/integrin signaling and with the potential to inhibit tumor growth and spread. 

Collaboration on transcapillary exchange with Professors Kathy Ferrara and Fitz-Roy Curry at the University of California Davis, and Professor Torfinn Taxt at UiB, focuses on methods for its measurement in genetically modified mice with subsequent use for studies in experimental tumors using dynamic contrast enhanced magnetic resonance (DCE-MRI) to study transcapillary exchange. The aim 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.

Research results

Inga Reigstad, Hilde Ytre-Hauge Smeland, Trude Skogstrand, Kristina Sortland, Caroline Schmid, Rolf Kåre Reed, Linda Stuhr: Stromal Integrin α11β1 Affects RM11 Prostate and 4T1 Breast Xenograft Tumors Differently, PLoS One. 2016 Mar 18;11(3).

Inga Reigstad, Kristina Sortland, Trude Skogstrand, Rolf K. Reed and Linda Stuhr: The Effect of Stromal Integrin β3-Deficiency on Two Different Tumors in Mice. Cancers 2016, 8(1), 14.

Plans for the future

The above projects will have natural extensions into the future as they develop further.

 

2016 Spring Interview

The Rolf Reed Group is focusing on research that leads to better insight of the tumor stroma and its dynamic properties, with the goal of altering therapeutic principles of solid tumors.

Could you tell us about your research on transcapillary exchange - what does it really mean?

"Transcapillary exchange describes the transport and transport processes taking place at the smallest blood vessels in the body, the microcirculation. This is where the nutrients are delivered by the arterial blood and then transported across the microvessels to reach the cells of the tissue while waste products are removed from the cells across the microcirculation and leave the tissue via the venous blood. Transcapillary exchange is determined by the pressure across the microvessels as well as the properties of these vessels. Our research has a particular focus on how the tissue via its structural molecules also can influence this transport by altering the biophysical properties of the tissue and thereby the pressures responsible for this transport. An immediate problem in cancers is a high tissue pressure that limits transport across the microvessels which also limits the delivery of cytostatic agents from the blood to the tumor. Our research is aimed at understanding what generates this high pressure and how the tumor microenvironment can be modified to enhance the transport."

How would you describe your findings so far?

"We have especially been working on the role of the collagen binding cellular receptors, the integrins, and how altered integrin-expression, i.e. collagen binding properties, will modify the microenvironment of the tumor and also the biophysical properties involved in transcapillary transport."

What groups of cancer patients is your work concentrated on?

"The research we are performing is not focused on a particular group of cancers. It is better characterized as “underpinning” since the aim is to understand basic mechanisms of transport across the microvascular barrier and its interaction with tissue stroma in general and with specific emphasis on the events that are altered in cancers."

PubMed Publications