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1.
Cardiovasc Res ; 115(5): 978-988, 2019 04 15.
Article in English | MEDLINE | ID: mdl-30753341

ABSTRACT

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO- levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.


Subject(s)
Angiogenesis Inhibitors/adverse effects , Cell Communication , Cell-Derived Microparticles/drug effects , Endothelial Cells/drug effects , Neoplasms/drug therapy , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Cardiotoxicity , Cell-Derived Microparticles/metabolism , Cell-Derived Microparticles/pathology , Cells, Cultured , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelin-1/metabolism , Female , Humans , Male , Middle Aged , Neoplasms/blood , Neoplasms/pathology , Nitric Oxide/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , Tyrosine/analogs & derivatives , Tyrosine/metabolism , Vascular Endothelial Growth Factor A/metabolism
2.
Br J Cancer ; 119(4): 487-491, 2018 08.
Article in English | MEDLINE | ID: mdl-30065256

ABSTRACT

Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier.  Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.


Subject(s)
Benzimidazoles/administration & dosage , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Neoplastic Cells, Circulating/pathology , Oxadiazoles/administration & dosage , Animals , Benzimidazoles/pharmacology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Count , Cluster Analysis , Disease Progression , Female , Gene Regulatory Networks/drug effects , Genetic Variation , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Male , Mice , Mutation , Neoplastic Cells, Circulating/chemistry , Neoplastic Cells, Circulating/drug effects , Oxadiazoles/pharmacology , Exome Sequencing , Xenograft Model Antitumor Assays
3.
Gut ; 66(7): 1268-1277, 2017 07.
Article in English | MEDLINE | ID: mdl-27618837

ABSTRACT

OBJECTIVE: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/ß-catenin pathway in liver cancer. DESIGN: Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/ß-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. RESULTS: Overexpression of the T-UCR uc.158- could differentiate Wnt/ß-catenin dependent HCC from normal liver and from ß-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158- was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of ß-catenin altered uc.158- expression in human malignant hepatocytes. uc.158- expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of ß-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/ß-catenin inhibitors. uc.158- expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158- reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158- sequence. Modulation of uc.158- changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158- inhibitor and anti-miR-193b rescued the effect of uc.158- inhibition on cell viability. CONCLUSIONS: We showed that uc.158- is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.


Subject(s)
Bile Duct Neoplasms/metabolism , Carcinoma, Hepatocellular/metabolism , Cholangiocarcinoma/metabolism , Conserved Sequence/genetics , Liver Neoplasms/metabolism , RNA, Untranslated/genetics , Wnt Signaling Pathway , Animals , Bile Duct Neoplasms/genetics , Carcinoma, Hepatocellular/genetics , Cholangiocarcinoma/genetics , Gene Expression Regulation, Neoplastic/genetics , Hepatocytes/metabolism , Humans , Liver Neoplasms/genetics , Mice, Knockout , MicroRNAs/metabolism , Neoplasms, Experimental , Transfection , beta Catenin/genetics , beta Catenin/metabolism
4.
Gastroenterol Clin North Am ; 45(3): 447-57, 2016 09.
Article in English | MEDLINE | ID: mdl-27546842

ABSTRACT

Small bowel adenocarcinomas (SBAs) are rare tumors, but their incidence is increasing. The most common primary location is the duodenum. Even though SBAs are more often sporadic, some diseases are risk factors. Early diagnosis of small bowel adenocarcinoma remains difficult, despite significant radiologic and endoscopic progress. After R0 surgical resection, the main prognostic factor is lymph node invasion. An international randomized trial (BALLAD [Benefit of Adjuvant Chemotherapy For Small Bowel Adenocarcinoma] study) will evaluate the benefit of adjuvant chemotherapy. For metastatic disease, retrospectives studies suggest that platinum-based chemotherapy is the most effective treatment. Phase II studies are ongoing to evaluate targeted therapy in metastatic SBA.


Subject(s)
Adenocarcinoma/genetics , Duodenal Neoplasms/genetics , Intestine, Small , Adenocarcinoma/diagnosis , Adenocarcinoma/metabolism , Adenocarcinoma/therapy , Adenomatous Polyposis Coli Protein/genetics , Capsule Endoscopy , Chemotherapy, Adjuvant , Digestive System Surgical Procedures , Double-Balloon Enteroscopy , Duodenal Neoplasms/diagnosis , Duodenal Neoplasms/metabolism , Duodenal Neoplasms/therapy , Humans , Intestinal Neoplasms/diagnosis , Intestinal Neoplasms/genetics , Intestinal Neoplasms/metabolism , Intestinal Neoplasms/therapy , Mutation , Phenotype , Prognosis , Proto-Oncogene Proteins p21(ras)/genetics , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Risk Factors , Tomography, X-Ray Computed , Tumor Suppressor Protein p53/metabolism , beta Catenin/metabolism
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