Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

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

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

“…Inhibition of TGF-β using inhibitors of TGF-β receptors or ligands, as well as antisense oligonucleotides or small molecule receptor kinase inhibitors, are under investigations and/or in clinical trials. 57 At present, the selection of patients with a more precise TGF-β-activated pathway could predict the therapeutic potential of TGF-β targeting. 58 In this line, measuring the level of TAp73 could predict which pathway, oncogenic or tumor suppressive, TGF-β is preferentially using at a specific time for each patient.…”

“…Protein samples (100 μg) were denatured at 95°C and subsequently separated by 12.5% SDS-PAGE gel electrophoresis. After transfer to nitrocellulose membrane and blocking with 5% milk, samples were probed with the following antibodies: rabbit polyclonal anti-mouse BGN LF-106 was a generous gift from Dr. Larry W Fisher, Bethesda, MD, USA 57 (1/100), rabbit monoclonal anti-Smad4 (Epitomics, Burlingame, CA, USA, 1/500), rabbit monoclonal pAkt (9271, Cell Signaling Technology, 1/500), rabbit monoclonal pSMAD2/3 (3101, Cell Signaling Technology, 1/500), rabbit monoclonal SMAD2/3 (3102, Cell Signaling Technology, 1/500), rabbit monoclonal p44/42 (4376, Cell Signaling Technology, 1/500), mouse β-tubulin (Sigma-Aldrich), rabbit polyclonal to N-cadherin (Abcam, Cambridge, Great-Britain, Ab18203, 1/400), goat polyclonal to ZEB1 (sc-10572, Santa Cruz, Nanterre, France, 1/100), rabbit polyclonal to SNAIL (ab-180714, Abcam, 1/100), mouse monoclonal anti-vimentin (Sigma-Aldrich, V6389, 1/100) and mouse monoclonal anti-E-cadherin (Life Technologies, 13-1900, 1/800). HRP-conjugated goat anti-mouse and goat anti-rabbit secondary antibodies and Immobilon Western Chemiluminescent HRP Substrate (Millipore) were used for detection.…”

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…Several mechanisms that are involved are summarized in Figure 2. TGF-β and GM-CSF play crucial roles in these processes (Costa-Silva et al, 2015;Neuzillet, de Gramont, et al, 2014;PylayevaGupta, Lee, Hajdu, Miller, & Bar-Sagi, 2012).…”

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

“…Multiple somatic events occur in PDAC carcinogenesis, such as p53 and SMAD4 inactivation (Lucas et al 2013, Neuzillet et al 2014. Indeed, chromosome breaks due to incomplete or inadequate DNA repair normally activate p53-dependent checkpoint controls and/or apoptosis to prevent tumor formation.…”