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

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.

Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients’ Outcome

“…Interestingly, several nanoparticle formulations for delivering drugs to hepatic stellate cells/CAFs and reprograming them as CAFs were tested successfully. These have become attractive targets for cancer therapies, especially in the liver [ 171 ].…”

“…Antisense oligonucleotides are short molecules of 13–25 nucleotides that downregulate TGF-β synthesis by interfering with mRNA function. There are several molecules such as AP11014 and AP15012 in preclinical development to treat tumors including CRC [ 171 ].…”

“…Several monoclonal antibodies such as 2G7, 1D11, lerdelimumab (CAT152), metelimumab (CAT152) and fresolimumab (GC1008) also neutralize the different isoforms of TGF-β [ 171 , 173 , 174 ]. Fresolimumab demonstrates acceptable safety and antitumor activity in melanoma and renal cell carcinoma, but no data exist for CRC patients [ 175 ].…”

“…Therefore, targeting PD-1 with TGF-β inhibitors is a biological rationale for cancer treatment. Various trials exploring combinations of PD-1/PD-L1 inhibitors are under development [ 171 ].…”

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

“…The contrary effects of reducing size on delivery and efficacy are regarded as “particle size dilemma” [ 266 ]. As other issues, tumor microenvironments such as stroma components should be considered [ 267 ]. As stromal components, extracellular matrices (ECMs) such as collagen fibers, and high interstitial pressure would restrict the diffusion of nanoparticles in tumor tissues; then, the use of digestive enzymes such as collagenase and hyaluronidase has been investigated to improve nanoparticle delivery and gene transfer efficiency [ 268 , 269 , 270 , 271 ].…”