Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer (80%), followed by cholangiocellular carcinoma (6%) and other rare types
A high degree of peritumoral myofibroblast infiltration and a high expression of α-smooth muscle actin (α-SMA) was associated with a significantly higher risk for HCC recurrence post resection [31,32]; osteopontin, a non-collagenous extracellular matrix (ECM) glycoprotein that stimulates the transition of fibroblasts to Cancer associated fibroblasts (CAF) and engages in tumor-associated-macrophage (TAM) signaling was found to be highly expressed in solid tumors, including HCC, in correlation to tumor grade, stage, future recurrence and metastasis [33,34,35,36,37]; in this vein, high osteopontin serum levels were associated with poor prognosis, Cells 2020, 9, x FOR PEER REVIEW
(M2-type macrophages) but directional crosstalk with stromal cells that include inflammatory cells like Tumor-associated macrophages (TAMs) (M2-type activated hepatic stellate cells (HSC)/myofibroblasts mutually sustain that theirmutually growth and expansion, resultingand in macrophages) and activated that
Summary
Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer (80%), followed by cholangiocellular carcinoma (6%) and other rare types. Activated myofibroblasts are the main collagen (and general ECM) producing cells in the liver and other organs They transdifferentiate from hepatic stellate cells (HSCs, liver sinusoidal pericytes) and portal fibroblasts and to a minor extent from bone-marrow-derived fibrocytes. These activated myofibroblasts are primary target cells for antifibrotic therapies but more recently for the treatment of (liver) cancer [2]. Apart from the immune cells in the tumor connective tissue that are skewed towards immunosuppression, the tumor myofibroblasts, that is, the cancer associated fibroblasts (CAF), support cancer growth by secreting pro-cancerous, immunosuppressive and pro-angiogenic ECM components and growth factors. CAF that can be correlated with tumor growth and aggressiveness and patient survival [10,16,17,18,19]
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