Browse

You are looking at 81 - 90 of 191 items for

  • Refine by access: Open Access content only x
Clear All
G Carreno Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by G Carreno in
Google Scholar
PubMed
Close
,
J K R Boult Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK

Search for other papers by J K R Boult in
Google Scholar
PubMed
Close
,
J Apps Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by J Apps in
Google Scholar
PubMed
Close
,
J M Gonzalez-Meljem Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Basic Research Department, Instituto Nacional de Geriatría, Mexico City, Mexico

Search for other papers by J M Gonzalez-Meljem in
Google Scholar
PubMed
Close
,
S Haston Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by S Haston in
Google Scholar
PubMed
Close
,
R Guiho Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by R Guiho in
Google Scholar
PubMed
Close
,
C Stache Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by C Stache in
Google Scholar
PubMed
Close
,
L S Danielson Division of Clinical Studies and Cancer Therapeutics Division, Paediatric Solid Tumour Biology and Therapeutics Team, The Institute of Cancer Research, London, UK

Search for other papers by L S Danielson in
Google Scholar
PubMed
Close
,
A Koers Division of Clinical Studies and Cancer Therapeutics Division, Paediatric Solid Tumour Biology and Therapeutics Team, The Institute of Cancer Research, London, UK

Search for other papers by A Koers in
Google Scholar
PubMed
Close
,
L M Smith Division of Clinical Studies and Cancer Therapeutics Division, Paediatric Solid Tumour Biology and Therapeutics Team, The Institute of Cancer Research, London, UK

Search for other papers by L M Smith in
Google Scholar
PubMed
Close
,
A Virasami Department of Histopathology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by A Virasami in
Google Scholar
PubMed
Close
,
L Panousopoulos Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by L Panousopoulos in
Google Scholar
PubMed
Close
,
M Buchfelder Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany

Search for other papers by M Buchfelder in
Google Scholar
PubMed
Close
,
T S Jacques Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Histopathology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by T S Jacques in
Google Scholar
PubMed
Close
,
L Chesler Division of Clinical Studies and Cancer Therapeutics Division, Paediatric Solid Tumour Biology and Therapeutics Team, The Institute of Cancer Research, London, UK

Search for other papers by L Chesler in
Google Scholar
PubMed
Close
,
S P Robinson Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK

Search for other papers by S P Robinson in
Google Scholar
PubMed
Close
, and
J P Martinez-Barbera Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK

Search for other papers by J P Martinez-Barbera in
Google Scholar
PubMed
Close

Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow-up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through MRI-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.

Open access
Dawei Wu Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Dawei Wu in
Google Scholar
PubMed
Close
,
Dongwei Lv Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Dongwei Lv in
Google Scholar
PubMed
Close
,
Ting Zhang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Ting Zhang in
Google Scholar
PubMed
Close
,
Lianying Guo Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Lianying Guo in
Google Scholar
PubMed
Close
,
Fangli Ma Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Fangli Ma in
Google Scholar
PubMed
Close
,
Caihua Zhang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Caihua Zhang in
Google Scholar
PubMed
Close
,
Guofeng Lv Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Guofeng Lv in
Google Scholar
PubMed
Close
, and
Lin Huang Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China

Search for other papers by Lin Huang in
Google Scholar
PubMed
Close

Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.

Open access
F Castinetti Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), and Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’Hypophyse HYPO, Marseille, France

Search for other papers by F Castinetti in
Google Scholar
PubMed
Close
,
F Albarel Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), and Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’Hypophyse HYPO, Marseille, France

Search for other papers by F Albarel in
Google Scholar
PubMed
Close
,
F Archambeaud Service de Médecine Interne B – Endocrinologie, Limoges Cedex, France

Search for other papers by F Archambeaud in
Google Scholar
PubMed
Close
,
J Bertherat Hôpital Cochin, Service d’Endocrinologie et Maladies Métaboliques, Paris Cedex 14, France

Search for other papers by J Bertherat in
Google Scholar
PubMed
Close
,
B Bouillet CHU Dijon, Hôpital François Mitterrand, Service d’Endocrinologie, Diabétologie, Maladies Métaboliques, Dijon Cedex, France
Unité INSERM LNC-UMR 1231, Université de Bourgogne, Dijon, France

Search for other papers by B Bouillet in
Google Scholar
PubMed
Close
,
P Buffier CHU Dijon, Hôpital François Mitterrand, Service d’Endocrinologie, Diabétologie, Maladies Métaboliques, Dijon Cedex, France

Search for other papers by P Buffier in
Google Scholar
PubMed
Close
,
C Briet Institut MITOVASC, INSERM U1083, Angers University, Department of Endocrinology, Diabetology and Nutrition, University Medical Center, Angers, France

Search for other papers by C Briet in
Google Scholar
PubMed
Close
,
B Cariou Department of Endocrinology, L’Institut du Thorax, CHU Nantes, Nantes, France

Search for other papers by B Cariou in
Google Scholar
PubMed
Close
,
Ph Caron CHU de Toulouse – Hôpital Larrey – Service d’Endocrinologie – Maladies métaboliques – Nutrition, TSA 30030, Toulouse Cedex 9, France

Search for other papers by Ph Caron in
Google Scholar
PubMed
Close
,
O Chabre CHU de Grenoble – Hôpital Albert Michallon, Service d’Endocrinologie-Diabétologie-Nutrition, Grenoble Cedex 9, France

Search for other papers by O Chabre in
Google Scholar
PubMed
Close
,
Ph Chanson Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, et UMR S-1185 Faculté de Médecine Paris-Sud, University of Paris-Saclay, Le Kremlin-Bicêtre, France

Search for other papers by Ph Chanson in
Google Scholar
PubMed
Close
,
C Cortet CHRU de Lille – Hopital Huriez, Service d’Endocrinologie, Lille Cedex, France

Search for other papers by C Cortet in
Google Scholar
PubMed
Close
,
C Do Cao CHRU de Lille – Hopital Huriez, Service d’Endocrinologie, Lille Cedex, France

Search for other papers by C Do Cao in
Google Scholar
PubMed
Close
,
D Drui Department of Endocrinology, L’Institut du Thorax, CHU Nantes, Nantes, France

Search for other papers by D Drui in
Google Scholar
PubMed
Close
,
M Haissaguerre CHU de Bordeaux – Hôpital du Haut Lévêque, Service d’Endocrinologie-Diabétologie et Maladies Métaboliques, Pessac Cedex, France

Search for other papers by M Haissaguerre in
Google Scholar
PubMed
Close
,
S Hescot Institut Curie, Oncologie Endocrinienne, Saint Cloud, France

Search for other papers by S Hescot in
Google Scholar
PubMed
Close
,
F Illouz Department of Endocrinology, Diabetes and Nutrition, Reference Centre of Rare Thyroid Disease, Hospital of Angers, Angers Cedex 09, France

Search for other papers by F Illouz in
Google Scholar
PubMed
Close
,
E Kuhn Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, et UMR S-1185 Faculté de Médecine Paris-Sud, University of Paris-Saclay, Le Kremlin-Bicêtre, France

Search for other papers by E Kuhn in
Google Scholar
PubMed
Close
,
N Lahlou Département d’Hormonologie Spécialisée, BPR-AS, Pannes, France

Search for other papers by N Lahlou in
Google Scholar
PubMed
Close
,
E Merlen CHRU de Lille – Hopital Huriez, Service d’Endocrinologie, Lille Cedex, France

Search for other papers by E Merlen in
Google Scholar
PubMed
Close
,
V Raverot Hospices Civils de Lyon, Laboratoire d’Hormonologie, Service de Biochimie et Biologie Moléculaire, Groupement Hospitalier Est, Lyon, France

Search for other papers by V Raverot in
Google Scholar
PubMed
Close
,
S Smati Department of Endocrinology, L’Institut du Thorax, CHU Nantes, Nantes, France

Search for other papers by S Smati in
Google Scholar
PubMed
Close
,
B Verges CHU Dijon, Hôpital François Mitterrand, Service d’Endocrinologie, Diabétologie, Maladies Métaboliques, Dijon Cedex, France
Unité INSERM LNC-UMR 1231, Université de Bourgogne, Dijon, France

Search for other papers by B Verges in
Google Scholar
PubMed
Close
, and
F Borson-Chazot Hospices Civils de Lyon, Fédération d’Endocrinologie, Université Claude Bernard Lyon 1, Lyon, France

Search for other papers by F Borson-Chazot in
Google Scholar
PubMed
Close

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using ‘common terminology criteria for adverse events’ (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

Open access
Sung Gwe Ahn Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Sung Gwe Ahn in
Google Scholar
PubMed
Close
,
Chang Ik Yoon Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Chang Ik Yoon in
Google Scholar
PubMed
Close
,
Jae Hoon Lee Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Jae Hoon Lee in
Google Scholar
PubMed
Close
,
Hye Sun Lee Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Hye Sun Lee in
Google Scholar
PubMed
Close
,
So Eun Park Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by So Eun Park in
Google Scholar
PubMed
Close
,
Yoon Jin Cha Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Yoon Jin Cha in
Google Scholar
PubMed
Close
,
Chihwan Cha Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Chihwan Cha in
Google Scholar
PubMed
Close
,
Soong June Bae Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Soong June Bae in
Google Scholar
PubMed
Close
,
Kyung-A Lee Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Kyung-A Lee in
Google Scholar
PubMed
Close
, and
Joon Jeong Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Search for other papers by Joon Jeong in
Google Scholar
PubMed
Close

On the basis of TP53 mutations and standardized uptake values (SUVs) from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), we sought to enhance our knowledge of the biology underlying low progesterone receptor (PR) expression in estrogen receptor (ER)-positive/human epidermal growth factor receptor-2 (HER2)-negative tumors. This study included 272 patients surgically treated for ER-positive, HER2-negative breast cancer and who had undergone TP53 gene sequencing. Of these, 229 patients also underwent 18F-FDG PET or PET/CT. Mutational analysis of exons 5–9 of the TP53 gene was conducted using PCR amplification and direct sequencing. The SUVs were measured using 18F-FDG-PET scan images. Twenty-eight (10.3%) tumors had a somatic TP53 mutation. The TP53 mutation rate was significantly higher in low-PR tumors than in high-PR tumors (17.1% vs 7.9%, P = 0.039). Low-PR tumors had significantly higher median SUVs than high-PR tumors (P = 0.046). The multivariable analysis revealed that SUV and age remained independent variables associated with low PR expression. An adverse impact of low PR expression on recurrence-free survival was observed in the multivariable Cox regression hazard model. We provide clinical evidence that genetic alteration of the TP53 gene and dysregulated glucose metabolism partly involve low PR expression in ER-positive and HER2-negative breast cancer.

Open access
Jonathan W Nyce ACGT Biotechnology, Collegeville, Pennsylvania, USA

Search for other papers by Jonathan W Nyce in
Google Scholar
PubMed
Close

We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.

Open access
Xianhui Ruan Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Search for other papers by Xianhui Ruan in
Google Scholar
PubMed
Close
,
Xianle Shi State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics and College of Life Sciences, Nankai University, Tianjin, China

Search for other papers by Xianle Shi in
Google Scholar
PubMed
Close
,
Qiman Dong State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics and College of Life Sciences, Nankai University, Tianjin, China

Search for other papers by Qiman Dong in
Google Scholar
PubMed
Close
,
Yang Yu Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Search for other papers by Yang Yu in
Google Scholar
PubMed
Close
,
Xiukun Hou Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Search for other papers by Xiukun Hou in
Google Scholar
PubMed
Close
,
Xinhao Song State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics and College of Life Sciences, Nankai University, Tianjin, China

Search for other papers by Xinhao Song in
Google Scholar
PubMed
Close
,
Xi Wei Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Search for other papers by Xi Wei in
Google Scholar
PubMed
Close
,
Lingyi Chen State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics and College of Life Sciences, Nankai University, Tianjin, China

Search for other papers by Lingyi Chen in
Google Scholar
PubMed
Close
, and
Ming Gao Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Search for other papers by Ming Gao in
Google Scholar
PubMed
Close

There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.

Open access
Simon Linder Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Search for other papers by Simon Linder in
Google Scholar
PubMed
Close
,
Henk G van der Poel Division of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Search for other papers by Henk G van der Poel in
Google Scholar
PubMed
Close
,
Andries M Bergman Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Search for other papers by Andries M Bergman in
Google Scholar
PubMed
Close
,
Wilbert Zwart Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

Search for other papers by Wilbert Zwart in
Google Scholar
PubMed
Close
, and
Stefan Prekovic Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Search for other papers by Stefan Prekovic in
Google Scholar
PubMed
Close

The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

Open access
Milena Doroszko Institute of Biomedicine, University of Turku, Turku, Finland

Search for other papers by Milena Doroszko in
Google Scholar
PubMed
Close
,
Marcin Chrusciel Institute of Biomedicine, University of Turku, Turku, Finland

Search for other papers by Marcin Chrusciel in
Google Scholar
PubMed
Close
,
Joanna Stelmaszewska Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland

Search for other papers by Joanna Stelmaszewska in
Google Scholar
PubMed
Close
,
Tomasz Slezak Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Tomasz Slezak in
Google Scholar
PubMed
Close
,
Slawomir Anisimowicz Center of Gynecology and Reproductive Endocrinology Artemida, Bialystok, Poland

Search for other papers by Slawomir Anisimowicz in
Google Scholar
PubMed
Close
,
Ursula Plöckinger Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité University Medicine Berlin, Berlin, Germany

Search for other papers by Ursula Plöckinger in
Google Scholar
PubMed
Close
,
Marcus Quinkler Endocrinology in Charlottenburg, Berlin, Germany
Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany

Search for other papers by Marcus Quinkler in
Google Scholar
PubMed
Close
,
Marco Bonomi Department of Clinical Sciences & Community Health, University of Milan, Milan, Italy

Search for other papers by Marco Bonomi in
Google Scholar
PubMed
Close
,
Slawomir Wolczynski Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland

Search for other papers by Slawomir Wolczynski in
Google Scholar
PubMed
Close
,
Ilpo Huhtaniemi Institute of Biomedicine, University of Turku, Turku, Finland
Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, U.K.

Search for other papers by Ilpo Huhtaniemi in
Google Scholar
PubMed
Close
,
Jorma Toppari Institute of Biomedicine, University of Turku, Turku, Finland
Department of Pediatrics, Turku University Hospital, Turku, Finland

Search for other papers by Jorma Toppari in
Google Scholar
PubMed
Close
, and
Nafis A Rahman Institute of Biomedicine, University of Turku, Turku, Finland
Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland

Search for other papers by Nafis A Rahman in
Google Scholar
PubMed
Close

Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse Cα1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin α promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11–13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

Open access
Paraskevi Xekouki Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK
Department of Endocrinology, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Paraskevi Xekouki in
Google Scholar
PubMed
Close
,
Emily J Lodge Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK
Department of Endocrinology and Diabetes, King’s College London, London, UK

Search for other papers by Emily J Lodge in
Google Scholar
PubMed
Close
,
Jakob Matschke Institute of Neuropathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Search for other papers by Jakob Matschke in
Google Scholar
PubMed
Close
,
Alice Santambrogio Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK
Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany

Search for other papers by Alice Santambrogio in
Google Scholar
PubMed
Close
,
John R Apps Birth Defects Research Centre, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Histopathology Department, Great Ormond Street Hospital NHS Trust, London, UK

Search for other papers by John R Apps in
Google Scholar
PubMed
Close
,
Ariane Sharif Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm U1172, Jean-Pierre Aubert Research Centre, Lille, France

Search for other papers by Ariane Sharif in
Google Scholar
PubMed
Close
,
Thomas S Jacques Birth Defects Research Centre, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Histopathology Department, Great Ormond Street Hospital NHS Trust, London, UK

Search for other papers by Thomas S Jacques in
Google Scholar
PubMed
Close
,
Simon Aylwin Department of Endocrinology, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Simon Aylwin in
Google Scholar
PubMed
Close
,
Vincent Prevot Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm U1172, Jean-Pierre Aubert Research Centre, Lille, France

Search for other papers by Vincent Prevot in
Google Scholar
PubMed
Close
,
Ran Li Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

Search for other papers by Ran Li in
Google Scholar
PubMed
Close
,
Jörg Flitsch Department of Neurosurgery, Hamburg University Medical Center, Hamburg, Germany

Search for other papers by Jörg Flitsch in
Google Scholar
PubMed
Close
,
Stefan R Bornstein Department of Endocrinology and Diabetes, King’s College London, London, UK
Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany

Search for other papers by Stefan R Bornstein in
Google Scholar
PubMed
Close
,
Marily Theodoropoulou Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

Search for other papers by Marily Theodoropoulou in
Google Scholar
PubMed
Close
, and
Cynthia L Andoniadou Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK
Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany

Search for other papers by Cynthia L Andoniadou in
Google Scholar
PubMed
Close

Tumours of the anterior pituitary can manifest from all endocrine cell types but the mechanisms for determining their specification are not known. The Hippo kinase cascade is a crucial signalling pathway regulating growth and cell fate in numerous organs. There is mounting evidence implicating this in tumour formation, where it is emerging as an anti-cancer target. We previously demonstrated activity of the Hippo kinase cascade in the mouse pituitary and nuclear association of its effectors YAP/TAZ with SOX2-expressing pituitary stem cells. Here, we sought to investigate whether these components are expressed in the human pituitary and if they are deregulated in human pituitary tumours. Analysis of pathway components by immunofluorescence reveals pathway activity during normal human pituitary development and in the adult gland. Poorly differentiated pituitary tumours (null-cell adenomas, adamantinomatous craniopharyngiomas (ACPs) and papillary craniopharyngiomas (PCPs)), displayed enhanced expression of pathway effectors YAP/TAZ. In contrast, differentiated adenomas displayed lower or absent levels. Knockdown of the kinase-encoding Lats1 in GH3 rat mammosomatotropinoma cells suppressed Prl and Gh promoter activity following an increase in YAP/TAZ levels. In conclusion, we have demonstrated activity of the Hippo kinase cascade in the human pituitary and association of high YAP/TAZ with repression of the differentiated state both in vitro and in vivo. Characterisation of this pathway in pituitary tumours is of potential prognostic value, opening up putative avenues for treatments.

Open access
Samuel M O’Toole William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

Search for other papers by Samuel M O’Toole in
Google Scholar
PubMed
Close
,
David S Watson William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by David S Watson in
Google Scholar
PubMed
Close
,
Tatiana V Novoselova William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Tatiana V Novoselova in
Google Scholar
PubMed
Close
,
Lisa E L Romano William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Lisa E L Romano in
Google Scholar
PubMed
Close
,
Peter J King William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Peter J King in
Google Scholar
PubMed
Close
,
Teisha Y Bradshaw William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Teisha Y Bradshaw in
Google Scholar
PubMed
Close
,
Clare L Thompson Institute of Bioengineering and School of Engineering and Material Sciences, Queen Mary University of London, London, UK

Search for other papers by Clare L Thompson in
Google Scholar
PubMed
Close
,
Martin M Knight Institute of Bioengineering and School of Engineering and Material Sciences, Queen Mary University of London, London, UK

Search for other papers by Martin M Knight in
Google Scholar
PubMed
Close
,
Tyson V Sharp Barts Cancer Institute, Queen Mary University of London, London, UK

Search for other papers by Tyson V Sharp in
Google Scholar
PubMed
Close
,
Michael R Barnes William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Michael R Barnes in
Google Scholar
PubMed
Close
,
Umasuthan Srirangalingam William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK
Department of Diabetes and Endocrinology, University College London Hospital, London, UK

Search for other papers by Umasuthan Srirangalingam in
Google Scholar
PubMed
Close
,
William M Drake Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

Search for other papers by William M Drake in
Google Scholar
PubMed
Close
, and
J Paul Chapple William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by J Paul Chapple in
Google Scholar
PubMed
Close

Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas – endocrine tumors of the adrenal medulla. This is concomitant with transcriptional changes within cilia-mediated signaling pathways that are associated with tumorigenesis generally and pheochromocytomas specifically. Importantly, cilia loss was most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a pheochromocytoma cell line derived from rat, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of an Aurora-A/HDAC6 cilia resorption pathway. We also show cilia loss drives dramatic transcriptional changes associated with proliferation and tumorigenesis. Our data provide evidence for primary cilia dysfunction contributing to pathogenesis of pheochromocytoma by a hypoxic/pseudohypoxic mechanism and implicates oncometabolites as ciliary regulators. This is important as pheochromocytomas can cause mortality by mechanisms including catecholamine production and malignant transformation, while hypoxia is a general feature of solid tumors. Moreover, pseudohypoxia-induced cilia resorption can be pharmacologically inhibited, suggesting potential for therapeutic intervention.

Open access