Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice

Nils Cordes,Tomas Friman,Kristofer Rubin,Renata Gustafsson,Åke Oldberg,Linda B Stuhr,Nils-Erik Heldin,Jean Chidiac,Rolf K Reed

doi:10.1371/journal.pone.0034082

Nils Cordes, Tomas Friman + Show 7 more

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https://doi.org/10.1371/journal.pone.0034082

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Journal: PloS one	Publication Date: Mar 30, 2012
Citations: 48	License type: CC BY 4.0

Affiliation: Uppsala University, Lund University, University of Bergen

Abstract

Stroma properties affect carcinoma physiology and direct malignant cell development. Here we present data showing that αVβ3 expressed by stromal cells is involved in the control of interstitial fluid pressure (IFP), extracellular volume (ECV) and collagen scaffold architecture in experimental murine carcinoma. IFP was elevated and ECV lowered in syngeneic CT26 colon and LM3 mammary carcinomas grown in integrin β3-deficient compared to wild-type BALB/c mice. Integrin β3-deficiency had no effect on carcinoma growth rate or on vascular morphology and function. Analyses by electron microscopy of carcinomas from integrin β3-deficient mice revealed a coarser and denser collagen network compared to carcinomas in wild-type littermates. Collagen fibers were built from heterogeneous and thicker collagen fibrils in carcinomas from integrin β3-deficient mice. The fibrotic extracellular matrix (ECM) did not correlate with increased macrophage infiltration in integrin β3-deficient mice bearing CT26 tumors, indicating that the fibrotic phenotype was not mediated by increased inflammation. In conclusion, we report that integrin β3-deficiency in tumor stroma led to an elevated IFP and lowered ECV that correlated with a more fibrotic ECM, underlining the role of the collagen network for carcinoma physiology.

Highlights

In addition to the malignant cells a carcinoma contains a connective tissue compartment, or stroma, which constitutes the microenvironment for the malignant cells
LM3 breast carcinomas were grown in female mice, whereas CT26 carcinomas were grown at equal ratios in male and female mice
We present data showing that absence of the integrin b3-subunit in the stroma of transplanted syngeneic LM3 mammary and CT26 colonic carcinomas results in a denser and coarser collagen network composed of thicker and irregular collagen fibrils

Summary

Introduction

In addition to the malignant cells a carcinoma contains a connective tissue compartment, or stroma, which constitutes the microenvironment for the malignant cells. Malignant cells must initiate or alternatively find a permissive microenvironment in order to establish themselves and grow. The microenvironment extracellular matrix (ECM) provides a scaffold for tumor growth and blood supply. The stroma typically exhibits distorted blood vessels, hypoxia, and acidic pH, as well as infiltrating myeloid cells and activated connective tissue cells that commonly produce a fibrotic ECM [1,2,3,4]. Formation of a stroma depends on signals from the malignant carcinoma cells and the non-malignant vascular, connective tissue and inflammatory cells. The stroma in turn influences the phenotype of the malignant cells [2,3,4]. Several experimental studies have pointed to the expression of collagen type I in the microenvironment and degree of crosslinking of collagen fibers as a determining factor in tumor progression including metastasis [4,5,6]

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