Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis

Abstract

Background Paracrine signaling between hepatic stellate cells (HSC) and liver endothelial cells (LEC) modulates fibrogenesis, angiogenesis, and portal hypertension. However, mechanisms regulating these processes are not fully defined. Sorafenib is a receptor tyrosine kinase inhibitor that blocks growth factor signaling in tumor cells but also displays important and not yet fully characterized effects on liver nonparenchymal cells including HSC and LEC. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSC and LEC and thereby regulates matrix and vascular changes associated with chronic liver injury. Results Complementary magnetic resonance elastography, micro-CT, and histochemical analyses indicate that sorafenib attenuates the changes in both matrix and vascular compartments that occur in response to bile-duct ligation induced liver injury in rats. Cell biology studies demonstrate that sorafenib markedly reduces cell to cell apposition and junctional complexes, thus reducing the proximity typically observed between these sinusoidal barrier cells. At the molecular level, sorafenib down-regulates angiopoietin-1 and fibronectin, both released by HSC in a manner dependent on the transcription factor KLF6, suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease. Conclusion Collectively, our results demonstrate that sorafenib inhibits both matrix restructuring and vascular remodeling that accompany chronic liver diseases and characterize cell and molecular mechanisms underlying this effect. These data may help to refine future therapies for advanced gastrointestinal and liver diseases characterized by abundant fibrosis and neovascularization.

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

“…Subsequent studies demonstrated sorafenib might reduce HSC proliferation, and inhibit the synthesis of fibrogenesis-related proteins and extracellular matrix (7,20,21). Sorafenib inhibits the KLF6/angiopoietin-1/fibronectin to disrupt the LSEC-HSC interactions, affecting the matrix reconstruction and vascular remodeling (22). Although sorafenib suppresses HSC by p-STAT3 inhibition in our study, a recent study suggested that sorafenib suppressed TGF-β1 induced epithelial-mesenchymal transition and apoptosis of hepatocytes, and also inhibited TGF-β1-induced STAT3 phosphorylation (23).…”

Evolving therapies for liver fibrosis

“…Antiangiogenic therapies have mitigated experimental liver fibrosis, mostly in models with a prominent sinusoidal component. However, antifibrotic effects were evident with polykinase inhibitors such as sunitinib and sorafenib that, apart from angiogenic VEGF or FGF receptors on LSECs, also target numerous other cells and kinases involved in proliferation, ECM turnover, and immune regulation (67,68). This lack of specificity may explain the finding that treatment with anti-VEGF antibody and an antagonist to integrin αvβ3, therapies that inhibit LSEC proliferation (but also affect the proliferation of endothelia of larger vessels) may worsen advanced biliary, perisinusoidal, and interstitial kidney fibrosis (69)(70)(71).…”

CD34 Expression in Noncancerous Liver Tissue Predicts Multicentric Recurrence of Hepatocellular Carcinoma

“…Sorafenib is a multikinase inhibitor compound approved for liver cancer and it inhibits tumor angiogenesis. In animal models, sorafenib also inhibits both matrix restructuring and vascular remodeling that accompanies chronic liver disease [31]. It may be a candidate for a new therapy to treat liver fibrosis and prevent carcinogenesis, but further investigation is needed before clinical application to humans.…”