Oncotarget

Reviews:

Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

Cindy Neuzillet, Armand de Gramont, Annemilaï Tijeras-Raballand, Louis de Mestier, Jérôme Cros, Sandrine Faivre and Eric Raymond _

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Oncotarget. 2014; 5:78-94. https://doi.org/10.18632/oncotarget.1569

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Abstract

Cindy Neuzillet1,*, Armand de Gramont1,2,*, Annemilaï Tijeras-Raballand2, Louis de Mestier1, Jérome Cros1,3, Sandrine Faivre1 and Eric Raymond1

1 INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP – PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, Clichy, France

2 AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France

3 Department of Pathology, Beaujon University Hospital (AP-HP – PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, Clichy, France

* These authors contributed equally to this work

Correspondence:

Eric Raymond, email:

Keywords: SMAD, stellate cells, extracellular matrix, EMT, TGF-β inhibitors.

Received: November 3, 2013 Accepted: December 18, 2013 Published: December 18, 2013

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-β (TGF-β) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-β pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-β signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-β pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-β as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-β inhibition therapy


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