Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May 8;15(5):e0232965.
doi: 10.1371/journal.pone.0232965. eCollection 2020.

The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach

Zarifeh Heidary  1 , Jafar Ghaisari  1 , Shiva Moein  2 , Shaghayegh Haghjooy Javanmard  3
Affiliations

The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach

Zarifeh Heidary et al. PLoS One. .

Abstract

Fibroblasts as key components of tumor microenvironment show different features in the interaction with cancer cells. Although, Normal fibroblasts demonstrate anti-tumor effects, cancer associated fibroblasts are principal participant in tumor growth and invasion. The ambiguity of fibroblasts function can be regarded as two heads of its behavioral spectrum and can be subjected for mathematical modeling to identify their switching behavior. In this research, an agent-based model of mutual interactions between fibroblast and cancer cell was created. The proposed model is based on nonlinear differential equations which describes biochemical reactions of the main factors involved in fibroblasts and cancer cells communication. Also, most of the model parameters are estimated using hybrid unscented Kalman filter. The interactions between two cell types are illustrated by the dynamic modeling of TGFβ and LIF pathways as well as their crosstalk. Using analytical and computational approaches, reciprocal effects of cancer cells and fibroblasts are constructed and the role of signaling molecules in tumor progression or prevention are determined. Finally, the model is validated using a set of experimental data. The proposed dynamic modeling might be useful for designing more efficient therapies in cancer metastasis treatment and prevention.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Molecular interactions between fibroblast and cancer cell.
Mutual interactions between two cell types include basic reactions of TGFβ and LIF pathways as well as their crosstalk. Communications between two cell types are mediated through LIF, TGFβ, SLIT2 and CXCL12 as transmission signals V1, V2, U1 and U2 respectively.
Fig 2
Fig 2. Model outputs of agent-based model compared with experimental data of GSE17708 dataset.
The graphs show the concentration change of CXCL12, SLIT2, LIF and SNAIL over the time by continuous black line and experimental data in several time points by red dots.
Fig 3
Fig 3
Principle Component Analysis (a) and heatmap clustering (b) demonstrated acceptable separation of samples in different time points.
See this image and copyright information in PMC

References

    1. Shimoda M, Mellody KT, and Orimo A, Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Seminars in cell & developmental biology. 2010; Elsevier. 10.1016/j.semcdb.2009.10.002 - DOI - PMC - PubMed
    1. Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, et al. Role of tumor microenvironment in tumorigenesis. Journal of Cancer. 2017; 8(5): 761 10.7150/jca.17648 - DOI - PMC - PubMed
    1. Kharaishvili G, Simkova D, Bouchalova K, Gachechiladze M, Narsia N, Bouchal J. The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance. Cancer cell international. 2014; 14(1):41 10.1186/1475-2867-14-41 - DOI - PMC - PubMed
    1. Lee SW, Kwak HS, Kang M-H, Park Y-Y, Jeong GS. Fibroblast-associated tumour microenvironment induces vascular structure-networked tumouroid. Scientific reports. 2018; 8(1): 2365 10.1038/s41598-018-20886-0 - DOI - PMC - PubMed
    1. Arina A, Idel C, Hyjek EM, Alegre M-L, Wang Y, Bindokas VP, et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proceedings of the National Academy of Sciences. 2016; 113(27): 7551–7556. doi: pnas.1600363113 - PMC - PubMed

MeSH terms