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Boulogne-Billancourt, France

Albert S.,Laboratoire Of Pharmacobiologie Des Agents Anticancereux | Albert S.,Bichat University Hospital | Riveiro M.E.,AAREC Filia Research | Halimi C.,Bichat University Hospital | And 7 more authors.
Head and Neck | Year: 2013

The human chemokine system includes approximately 48 chemokines and 19 chemokine receptors. The CXCL12/CXCR4 system is one of the most frequently studied that is also found overexpressed in a large variety of tumors. The CXCL12/CXCR4 axis has been increasingly identified as an important target in cancer growth, metastasis, relapse, and resistance to therapy. In this review, we highlight current knowledge of the molecular mechanisms involving chemokines CXCL12/CXCR4 and their consequences in head and neck squamous cell carcinoma (HNSCC). Overexpression of CXCL12/CXCR4 in HNSCC appears to activate cellular functions, including motility, invasion, and metastatic processes. Current findings suggest that CXCR4 and epithelial-mesenchymal transition markers are associated with tumor aggressiveness and a poor prognosis, and may be suitable biomarkers for head and neck tumors with high metastatic potential. Furthermore, knowledge of the role of CXCR4 in HNSCC could influence the development of new targeted therapies for treatment, aimed at improving the prognosis of this disease. © 2013 Wiley Periodicals, Inc.

Cohen R.,French Institute of Health and Medical Research | Neuzillet C.,French Institute of Health and Medical Research | Neuzillet C.,Henri Mondor University Hospital | Tijeras-Raballand A.,AAREC Filia Research | And 3 more authors.
Oncotarget | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

Neuzillet C.,French Institute of Health and Medical Research | de Gramont A.,French Institute of Health and Medical Research | de Gramont A.,AAREC Filia Research | Tijeras-Raballand A.,AAREC Filia Research | And 5 more authors.
Oncotarget | Year: 2014

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-ß (TGF-ß) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-ß pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-ß 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-ß 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-ß as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-ß inhibition therapy.

Neuzillet C.,French Institute of Health and Medical Research | Tijeras-Raballand A.,AAREC Filia Research | Cohen R.,AAREC Filia Research | Cros J.,University Paris Diderot | And 3 more authors.
Pharmacology and Therapeutics | Year: 2015

The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings. © 2014 The Authors. Published by Elsevier Inc.

Dings R.P.M.,University of Minnesota | Miller M.C.,University of Minnesota | Nesmelova I.,University of Minnesota | Astorgues-Xerri L.,French Institute of Health and Medical Research | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2012

Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, 15N- 1H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118. © 2012 American Chemical Society.

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