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한국과학기술연구원(KIST)

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Bioeng. Transl. Med., First published: 23 December 2021 | https://doi.org/10.1002/btm2.10286 TIMP-1-expressing breast tumor spheroids for the evaluation of drug penetration and efficacy

In Yeong Bae^a,*, Wooshik Choi^a,*, Seung Ja Oh^a,c, Chansoo Kim^b,and Sang-Heon Kim^a,c,#

^aCenter for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
^bAI Lab., Computational Science Center & ESRI, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
^cDepartment of Biomedical Engineering, KIST school, Korea University of Science and Technology, Seoul, 02792, Republic of Korea

^*These authors contributed equally to this work.

^#Corresponding author.

Abstract

Abundance of stromal cells and extracellular matrix (ECM) is observed in breast cancer, acting as a barrier for drug penetration and presenting a key issue for developing efficient therapeutics. In this study, we aimed to develop a 3D multicellular tumor model comprising cancer and stromal cells that could effectively mimic the drug resistance properties of breast cancer. Three different types of spheroid models were designed by co-culturing breast cancer cells (MDA-MB-231) with three different types of stromal cells: adipose-derived stromal cells (hASCs), bone marrow stromal cells (hBMSCs), or dermal fibroblasts (hDFs). Compared with other models, in the hASC co-culture model, tissue inhibitor of metalloproteinases-1 (TIMP-1) was highly expressed and the activity of matrix metalloproteinases was decreased, resulting in a higher ECM deposition on the spheroid surfaces. This spheroid model showed less drug penetration and treatment efficacy than the other models. TIMP-1 silencing in hASCs reduced ECM protein expression and increased drug penetration and vulnerability. A quantitative structure-activity relationship study using multiple linear regression drew linear relationships between the chemical properties of drugs and experimentally determined permeability values. Drugs that did not match the drug-likeness rules exhibited lower permeability in the 3D tumor model. Taken together, our findings indicate that this 3D multicellular tumor model may be used as a reliable platform for efficiently screening therapeutics agents for solid tumors.

Keywords: 3D multicellular tumor spheroid, Adipose-derived stromal cells, Extracellular matrix, Collagen type-1, Tissue inhibitor of metalloproteinases-1, Multiple linear regression

논문정보

형식Research article
게재일2021년 12월 (BRIC 등록일 2021-12-31)
연구진국내 연구진
분야 의약학 > 재생의학

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