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

Dominique Thabut, Chittaranjan Routray, Gwen Lomberk, Uday Shergill, Kevin Glaser, Robert C Huebert, Leena Patel, Tetyana Masyuk, Boris Blechacz, Andrew Vercnocke, Erik Ritman, Richard Lorne Ehman, Raul Urrutia, Vijay Shah

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Paracrine signaling between hepatic stellate cells (HSCs) and liver endothelial cells (LECs) 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 HSCs and LECs. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSCs and LECs and thereby regulates matrix and vascular changes associated with chronic liver injury. Complementary magnetic resonance elastography, micro-computed tomography, 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-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 HSCs in a manner dependent on the transcription factor Kruppel-like factor 6 , suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease. Conclusion: Collectively, the results of this study 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.

Original languageEnglish (US)
Pages (from-to)573-585
Number of pages13
JournalHepatology
Volume54
Issue number2
DOIs
StatePublished - Aug 2011

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Liver Cirrhosis
Blood Vessels
Hepatic Stellate Cells
Liver
Paracrine Communication
Liver Diseases
Endothelial Cells
Chronic Disease
Kruppel-Like Transcription Factors
Angiopoietin-1
Elasticity Imaging Techniques
Gastrointestinal Diseases
Wounds and Injuries
Receptor Protein-Tyrosine Kinases
Portal Hypertension
Bile Ducts
Fibronectins
Ligation
Cell Biology
sorafenib

ASJC Scopus subject areas

  • Hepatology

Cite this

Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. / Thabut, Dominique; Routray, Chittaranjan; Lomberk, Gwen; Shergill, Uday; Glaser, Kevin; Huebert, Robert C; Patel, Leena; Masyuk, Tetyana; Blechacz, Boris; Vercnocke, Andrew; Ritman, Erik; Ehman, Richard Lorne; Urrutia, Raul; Shah, Vijay.

In: Hepatology, Vol. 54, No. 2, 08.2011, p. 573-585.

Research output: Contribution to journalArticle

Thabut, D, Routray, C, Lomberk, G, Shergill, U, Glaser, K, Huebert, RC, Patel, L, Masyuk, T, Blechacz, B, Vercnocke, A, Ritman, E, Ehman, RL, Urrutia, R & Shah, V 2011, 'Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis', Hepatology, vol. 54, no. 2, pp. 573-585. https://doi.org/10.1002/hep.24427
Thabut, Dominique ; Routray, Chittaranjan ; Lomberk, Gwen ; Shergill, Uday ; Glaser, Kevin ; Huebert, Robert C ; Patel, Leena ; Masyuk, Tetyana ; Blechacz, Boris ; Vercnocke, Andrew ; Ritman, Erik ; Ehman, Richard Lorne ; Urrutia, Raul ; Shah, Vijay. / Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. In: Hepatology. 2011 ; Vol. 54, No. 2. pp. 573-585.
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