RESUMO
Pancreatic cancer is a highly lethal cancer characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease, and interactions between cancer and stromal cells are critical for pancreatic cancer development and progression. Mesenchymal stromal cells [MSCs] exhibit preferential tropism to primary and metastatic tumor sites and may either suppress or support tumor growth. Although MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSCs significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSCs create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis, including interleukin (IL)-6, IL-8, vascular endothelial growth factor and activation of STAT3 signaling in tumor cells. IL-6 released by MSCs was largely responsible for the pro-tumorigenic effects of MSCs. Knockdown of IL-6 expression in MSCs by small interfering RNA (siRNA) abolished the MSC growth-promoting effect in vitro, reducing tumor cell proliferation and clonogenic potential. In addition, in a heterotopic nude mouse model of human pancreatic tumor xenografts, blockade of IL-6 with the anti-IL-6 receptor antibody, tocilizumab, or of its downstream effector STAT3 with the small molecule STAT3 inhibitor S3I-201, abrogated MSC-mediated tumor promotion and delayed tumor formation significantly. Our data demonstrate that MSCs promote pancreatic cancer growth, with IL-6 produced by MSCs playing a pivotal role.
Assuntos
Interleucina-6/metabolismo , Células-Tronco Mesenquimais , Neoplasias Pancreáticas , Animais , Medula Óssea/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias PancreáticasRESUMO
The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation.
RESUMO
UCHL3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme involved in the homologous recombination repair mechanism of double-strand breaks (DBS) of the DNA. Multiple studies indicated that UCHL3 inhibitors could be used in combination therapy with high therapeutic efficacy against cancer thus highlighting the validity of directing research against UCHL3 as a druggable target in oncology. In this study, a combination of virtual screening methods was utilized to identify new potential UCHL3 inhibitors. A series of UCHL3 ligands were identified by applying a combination of cheminformatics and molecular modeling filtration techniques to a ChemBl database of over two million small molecules viz. Lipinski's Rule of Five, Veber's rule, pharmacophore model, Hierarchical molecular docking, Pan-assay Interference Compounds (PAINS) alerts, toxicity filter, and single-point Molecular mechanics Poisson/Boltzmann surface area (MM/PBSA) docking pose rescoring. This multi-layer filtration strategy led to the identification of twenty-one compounds as potential UCHL3 inhibitors that were subsequently subjected to a 50 ns molecular dynamics (MD) simulations predict the stability of their ligand-protein complexes. Furthermore, MM/PBSA calculations based on MD trajectories were performed, and the energy contribution per residue to the binding energy was calculated. Three compounds, 1, 2 and 3, were finally recognized as having the highest potential of being UCHL3 inhibitors. Therefore, those were used for binding mode analysis to the UCHL3 active site, leading to identification of four residues as key for binding viz. Pro8, Leu55, Val166, and Leu168.Communicated by Ramaswamy H. Sarma.
Assuntos
Simulação de Dinâmica Molecular , Neoplasias , Detecção Precoce de Câncer , Humanos , Ligantes , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Reparo de DNA por Recombinação , Ubiquitina TiolesteraseRESUMO
Ependymomas are rare central nervous system tumours that can arise in the brain's supratentorial region or posterior fossa, or in the spinal cord. In 1924, Percival Bailey published the first comprehensive study of ependymomas. Since then, and especially over the past 10 years, our understanding of ependymomas has grown exponentially. In this Review, we discuss the evolution in knowledge regarding ependymoma subgroups and the resultant clinical implications. We also discuss key oncogenic and tumour suppressor signalling pathways that regulate tumour growth, the role of epigenetic dysregulation in the biology of ependymomas, and the various biological features of ependymoma tumorigenesis, including cell immortalization, stem cell-like properties, the tumour microenvironment and metastasis. We further review the limitations of current therapies such as relapse, radiation-induced cognitive deficits and chemotherapy resistance. Finally, we highlight next-generation therapies that are actively being explored, including tyrosine kinase inhibitors, telomerase inhibitors, anti-angiogenesis agents and immunotherapy.
Assuntos
Ependimoma , Recidiva Local de Neoplasia , Biologia , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/terapia , Humanos , Oncogenes , Microambiente TumoralRESUMO
Lymphopenia is considered one of the most characteristic clinical features of the coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects host cells via the interaction of its spike protein with the human angiotensin-converting enzyme 2 (hACE2) receptor. Since T lymphocytes display a very low expression level of hACE2, a novel receptor might be involved in the entry of SARS-CoV-2 into T cells. The transmembrane glycoprotein CD147 is highly expressed by activated T lymphocytes, and was recently proposed as a probable route for SARS-CoV-2 invasion. To understand the molecular basis of the potential interaction of SARS-CoV-2 to CD147, we have investigated the binding of the viral spike protein to this receptor in-silico. The results showed that this binding is dominated by electrostatic interactions involving residues Arg403, Asn481, and the backbone of Gly502. The overall binding arrangement shows the CD147 C-terminal domain interacting with the spike external subdomain in the grove between the short antiparallel ß strands, ß1' and ß2', and the small helix α1'. This proposed interaction was further confirmed using MD simulation and binding free energy calculation. These data contribute to a better understanding of the mechanism of infection of SARS-CoV-2 to T lymphocytes and could provide valuable insights for the rational design of adjuvant treatment for COVID-19. Communicated by Ramaswamy H. Sarma.
Assuntos
COVID-19 , Linfopenia , Basigina , Humanos , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the "message-address model" for KOP efficacy and selectivity by binding to Glu297.