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Paracrine activation of hepatic stellate cells in platelet‐derived growth factor C transgenic mice: Evidence for stromal induction of hepatocellular carcinoma
Author(s) -
Wright Jocelyn H.,
Johnson Melissa M.,
ShimizuAlbergine Masami,
Bauer Renay L.,
Hayes Brian J.,
Surapisitchat James,
Hudkins Kelly L.,
Riehle Kimberly J.,
Johnson Simon C.,
Yeh Matthew M.,
Bammler Theodor K.,
Beyer Richard P.,
Gilbertson Debra G.,
Alpers Charles E.,
Fausto Nelson,
Campbell Jean S.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28421
Subject(s) - hepatic stellate cell , cancer research , stromal cell , paracrine signalling , hepatocyte growth factor , biology , platelet derived growth factor receptor , growth factor , platelet derived growth factor , nonalcoholic fatty liver disease , cirrhosis , fibrosis , pathology , medicine , fatty liver , endocrinology , receptor , disease
Cirrhosis is the primary risk factor for the development of hepatocellular carcinoma (HCC), yet the mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood. Using a mouse model that recapitulates many aspects of the pathophysiology of human liver disease, we explored the mechanisms by which changes in the liver microenvironment induce dysplasia and HCC. Hepatic expression of platelet‐derived growth factor C (PDGF‐C ) induces progressive fibrosis, chronic inflammation, neoangiogenesis and sinusoidal congestion, as well as global changes in gene expression. Using reporter mice, immunofluorescence, immunohistochemistry and liver cell isolation, we demonstrate that receptors for PDGF‐CC are localized on hepatic stellate cells (HSCs), which proliferate, and transform into myofibroblast‐like cells that deposit extracellular matrix and lead to production of growth factors and cytokines. We demonstrate induction of cytokine genes at 2 months, and stromal cell‐derived hepatocyte growth factors that coincide with the onset of dysplasia at 4 months. Our results support a paracrine signaling model wherein hepatocyte‐derived PDGF‐C stimulates widespread HSC activation throughout the liver leading to chronic inflammation, liver injury and architectural changes. These complex changes to the liver microenvironment precede the development of HCC. Further, increased PDGF‐CC levels were observed in livers of patients with nonalcoholic fatty steatohepatitis and correlate with the stage of disease, suggesting a role for this growth factor in chronic liver disease in humans. PDGF‐C transgenic mice provide a unique model for the in vivo study of tumor–stromal interactions in the liver.