Stromal fibroblasts regulate microvascular-like network architecture in a bioengineered breast tumour angiogenesis model

Maria K Koch; Anna Jaeschke; Berline Murekatete; Akhilandeshwari Ravichandran; Mikhail Tsurkan; Carsten Werner; Patsy Soon; Dietmar W Hutmacher; Larisa M Haupt; Laura J Bray

doi:10.1016/j.actbio.2020.07.036

Stromal fibroblasts regulate microvascular-like network architecture in a bioengineered breast tumour angiogenesis model

Acta Biomater. 2020 Sep 15:114:256-269. doi: 10.1016/j.actbio.2020.07.036. Epub 2020 Jul 21.

Affiliations

¹ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia; School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia.
² Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia.
³ Leibniz Institute of Polymer Research Dresden, Germany.
⁴ South Western Sydney Clinical School, University of New South Wales, Australia; Department of Surgery, Bankstown Hospital, South Western Sydney Local Health District, Australia; Ingham Institute for Applied Medical Research, Australia.
⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia; School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Australia.
⁶ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia; Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Australia.
⁷ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia; School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia. Electronic address: laura.bray@qut.edu.au.

PMID: 32707406
DOI: 10.1016/j.actbio.2020.07.036

Abstract

The plasticity of the tumour microenvironment is a key contributor to cancer development and progression. Here, we present a bioengineered breast tumour angiogenesis model comprised of mammary derived epithelial, endothelial and fibroblast cells, to dissect the mechanisms of cancer-associated fibroblasts (CAFs) on microvascular-like network formation and epithelial spheroid morphology. Primary patient-derived mammary endothelial cells, normal breast fibroblasts (NBF, patient matched) and CAFs were cultured within three-dimensional (3D) semi-synthetic hydrogels where CAFs promoted an increase in the density and morphology of the microvascular-like network. The mammary microenvironment also increased the number of MCF-10a epithelial spheroids when compared with a non-mammary microenvironment, and a malignant mammary microenvironment resulted in further morphological differences in the epithelial spheroids. The morphological changes observed following interactions between breast CAFs and endothelial cells, highlight the plasticity of the malignant stroma in tumour vascularisation. Our in vitro bioengineered breast cancer microenvironment provides a robust model to study cell-cell and cell-matrix interactions. Statement of Significance In recent years there has been an increase in the sophistication of 3D culture models, however less attention has been paid to the cell source utilised. In this study, we describe the influence of a normal and malignant stromal microenvironment on vessel-like behaviour in a 3D model. Using a semi-synthetic hydrogel, we studied the effects of mammary-derived cancer-associated fibroblasts and normal fibroblasts on human umbilical vein endothelial cells or human mammary microvascular endothelial cells. An increase in vessel-like network and epithelial cell density was seen in a mammary versus non-mammary microenvironment. This study highlights the importance of using tissue-specific endothelial cells in cancer research and demonstrates the microenvironmental impact of fibroblasts on endothelial and epithelial growth and morphology.

Keywords: Angiogenesis; Breast cancer; Cancer-associated fibroblasts; Hydrogel; Tumour microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms*
Breast*
Fibroblasts
Humans
Neovascularization, Pathologic
Stromal Cells
Tumor Microenvironment