Modeling triple-negative breast cancer heterogeneity: Effects of stromal macrophages, fibroblasts and tumor vasculature

JOURNAL OF THEORETICAL BIOLOGY

卷:452

Article

Norton, Kerri-Ann^1,5  Jin, Kideok^1,4  Popel, Aleksander S.^1,2,3 

[1] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21218 USA

[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA

[4] Albany Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Albany, NY USA

[5] Bard Coll, Dept Sci Math & Comp, Comp Sci Program, Annandale on Hudson, NY 12504 USA

关键词: Tumor;    Microenvironment;    Immune cells;    Angiogenesis;    Cancer stem cells;    Hypoxia;   

DOI  :  10.1016/j.jtbi.2018.05.003

来源: Elsevier

【 摘 要 】

A hallmark of breast tumors is its spatial heterogeneity that includes its distribution of cancer stem cells and progenitor cells, but also heterogeneity in the tumor microenvironment. In this study we focus on the contributions of stromal cells, specifically macrophages, fibroblasts, and endothelial cells on tumor progression. We develop a computational model of triple-negative breast cancer based on our previous work and expand it to include macrophage infiltration, fibroblasts, and angiogenesis. In vitro studies have shown that the secretomes of tumor-educated macrophages and fibroblasts increase both the migration and proliferation rates of triple-negative breast cancer cells. In vivo studies also demonstrated that blocking signaling of selected secreted factors inhibits tumor growth and metastasis in mouse xenograft models. We investigate the influences of increased migration and proliferation rates on tumor growth, the effect of the presence on fibroblasts or macrophages on growth and morphology, and the contributions of macrophage infiltration on tumor growth. We find that while the presence of macrophages increases overall tumor growth, the increase in macrophage infiltration does not substantially increase tumor growth and can even stifle tumor growth at excessive rates. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

Free