Journal
CANCERS
Volume 14, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/cancers14092077
Keywords
pancreatic cancer; organoid; tumor microenvironment; cancer-associated fibroblast; extracellular matrix
Categories
Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health Welfare, Korea [HR16C0002, HI16C1634, HI21C0651]
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Science, ICT & Future Planning, Korea [NRF-2017R1C1B2003970, 2019M3A9H2032424, 2020R1I1A1A01066458]
- Technology Innovation Program (Industrial Strategic Technology Development Program-3D-TissueChip Based Drug Discovery Platform Program) - Ministry of Trade, Industry & Energy (MOTIE, Korea) [20009773]
- Advanced Demonstration Support Project through the Daegu-gyeongbuk Medical Innovation Foundation - Ministry of Health Welfare [DGMIF-HW-2020-002]
- Ajou University of Medical Center
- National Research Foundation of Korea [2020R1I1A1A01066458] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Pancreatic cancer is highly resistant to anticancer drugs due to its complex microenvironment, particularly the extracellular matrix components produced by cancer-associated fibroblasts (CAFs). In this study, a novel CAF-integrated pancreatic cancer organoid (CIPCO) model was developed to mimic the tumor microenvironment, which showed similar gene expression and pathological characteristics to human cancer tissue. This model has the potential to be used for preclinical studies and the development of individualized therapies.
Simple Summary Pancreatic cancer tissue is resistant to anticancer drugs because of its complex microenvironment. Cancer-associated fibroblasts (CAFs) are an important source of extracellular matrix components, which alter the physical and chemical properties of pancreatic tissue, thus impairing effective intratumoral drug delivery and resulting in resistance to conventional chemotherapy. In this study, we developed a novel CAF-integrated pancreatic cancer organoid (CIPCO) model that can mimic the tumor microenvironment and confirmed that the gene expression and pathological characteristics of CIPCO are similar to those of human cancer tissue. The organoid model could serve as a preclinical model for developing individualized therapies. Pancreatic cancer is a devastating disease and is highly resistant to anticancer drugs because of its complex microenvironment. Cancer-associated fibroblasts (CAFs) are an important source of extracellular matrix (ECM) components, which alter the physical and chemical properties of pancreatic tissue, thus impairing effective intratumoral drug delivery and resulting in resistance to conventional chemotherapy. The objective of this study was to develop a new cancer organoid model, including a fibrous tumor microenvironment (TME) using CAFs. The CAF-integrated pancreatic cancer organoid (CIPCO) model developed in this study histologically mimicked human pancreatic cancer and included ECM production by CAFs. The cancer cell-CAF interaction in the CIPCO promoted epithelial-mesenchymal transition of cancer cells, which was reversed by CAF inhibition using all-trans retinoic acid. Deposition of newly synthesized collagen I in the CIPCO disturbed the delivery of gemcitabine to cancer cells, and treatment with collagenase increased the cytotoxic effect of gemcitabine. This model may lead to the development of next-generation cancer organoid models recapitulating the fibrous TME.
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