Accumulation of mechanical forces in tumors is related to hyaluronan content and tissue stiffness

Chrysovalantis Voutouri,Triantafyllos Stylianopoulos,Krishna Garikipati

doi:10.1371/journal.pone.0193801

Chrysovalantis Voutouri, Triantafyllos Stylianopoulos + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0193801

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Journal: PloS one	Publication Date: Mar 21, 2018
Citations: 52	License type: CC BY 4.0

Affiliation: University of Cyprus

Abstract

Hyaluronan is abundant in the extracellular matrix of many desmoplastic tumors and determines in large part the tumor biochemical and mechanical microenvironment. Additionally, it has been identified as one of the major physiological barriers to the effective delivery of drugs to solid tumors and its targeting with the use of pharmaceutical agents has shown to decompress tumor blood vessels, and thus improve tumor perfusion and efficacy of cytotoxic drugs. In this study, we investigated the contribution of hyaluronan to the accumulation of mechanical forces in tumors. Using experimental data from two orthotopic breast tumor models and treating tumors with two clinically approved anti-fibrotic drugs (tranilast and pirfenidone), we found that accumulation of growth-induced, residual forces in tumors are associated with hyaluronan content. Furthermore, mechanical characterization of the tumors revealed a good correlation of the accumulated forces with the elastic modulus of the tissue. Our results provide important insights on the mechano-pathology of solid tumors and can be used for the design of therapeutic strategies that target hyaluronan.

Highlights

Solid tumors often stiffen as they grow at the expense of the surrounding host tissue
The three tissue-level types of solid stress that are developed in tumors are: i) stress applied externally to the tumor by the host tissue, ii) growth-induced stress, which is accumulated in the tumor and remains even if the tumor is excised, and iii) swelling stress owing to the swelling behavior of the hyaluronan [6]
Despite the crucial role that mechanical forces play in tumor growth and therapy, the study of the biomechanical behavior of solid tumors remains a relatively unexplored area of research as least compared to the biomechanics of other connective tissues, such as blood vessel, heart, Fig 6

Summary

Introduction

Solid tumors often stiffen as they grow at the expense of the surrounding host tissue. Tissue stiffening is caused by an increase in the amount of cancer cells, stromal cells and the extracellular matrix constituents, mainly collagen and hyaluronan. Cancer cells divide faster than normal cells, the tumor becomes stiffer and displaces the surrounding normal tissue, which allows tumor progression. The three tissue-level types of solid stress (i.e., stress of the solid components) that are developed in tumors are: i) stress applied externally to the tumor by the host tissue, ii) growth-induced (or residual) stress, which is accumulated in the tumor and remains even if the tumor is excised, and iii) swelling stress owing to the swelling behavior of the hyaluronan [6].

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