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Review

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

by 1,2 and 1,3,*
1
Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, D-55131 Mainz, Germany
2
Deptartment of Medicine 1, University Medical Center, D-55131 Mainz, Germany
3
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(9), 2027; https://doi.org/10.3390/cells9092027
Received: 17 August 2020 / Revised: 26 August 2020 / Accepted: 31 August 2020 / Published: 3 September 2020
(This article belongs to the Special Issue Nanoparticles in Cancer Immunotherapy)
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver. View Full-Text
Keywords: nanoparticle; tumor microenvironment (TME); extracellular matrix (ECM); immune suppression; therapy; tumor-associated-macrophage (TAM); anti-fibrotic; siRNA; anti-fibrotic; HCC; desmoplastic stroma; platelet-derived growth factor (PDGF) nanoparticle; tumor microenvironment (TME); extracellular matrix (ECM); immune suppression; therapy; tumor-associated-macrophage (TAM); anti-fibrotic; siRNA; anti-fibrotic; HCC; desmoplastic stroma; platelet-derived growth factor (PDGF)
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MDPI and ACS Style

Kaps, L.; Schuppan, D. Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells 2020, 9, 2027. https://doi.org/10.3390/cells9092027

AMA Style

Kaps L, Schuppan D. Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells. 2020; 9(9):2027. https://doi.org/10.3390/cells9092027

Chicago/Turabian Style

Kaps, Leonard, and Detlef Schuppan. 2020. "Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers" Cells 9, no. 9: 2027. https://doi.org/10.3390/cells9092027

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