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Role of circulating tumor cell spheroids in drug resistance

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Cancer Drug Resistance 2019年第3期2卷 762-772页

作者： Gerhard Hamilton barbara rath Department of Surgery Medical University of ViennaVienna A-1090Austria

Cancer cell spheroids are used for drug screening as these three-dimensional(3D)assemblies recapitulate tumors more realistic than the widely employed 2D in vitro *** drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug *** tumor cells(CTCs)effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer(SCLC)and in other cancer patients with high tumor *** are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal *** may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic *** our lab we have obtained 9 permanent SCLC CTC cell lines(BHGc7,BHGc10,BHGc16,BHGc26,BHGc27,BHGc50,BHGc59,BHGc71,and UHGc5)of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids,termed *** aggregates were shown to exhibit high drug resistance compared to the corresponding single cell *** increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in *** drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low ***,we have detected such tumorospheres in non-small-cell lung cancer(NSCLC)patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

关键词： Cancer spheroid circulating tumor cells small cell lung cancer non-small-cell lung cancer transformation dormancy

Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

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Cancer Drug Resistance 2020年第2期3卷 171-178页

作者： barbara rath Adelina Plangger Gerhard Hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1090Austria

Mutated or rearranged driver kinases in non-small cell lung cancer(NSCLC)cells are clinically amenable to treatment with tyrosine kinase inhibitors(TKIs)resulting in prolonged survival and significant benefit compared to cytotoxic *** most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase,which can be blocked by a range of specific TKIs in *** clinics,resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases(on-target)or alternative pathways circumventing the original kinase(off-target)alterations.A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer(SCLC)in up to 14%of cases,which,in general,is accompanied by resistance to the original *** transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive *** transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug *** conclusion,the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

关键词： Lung cancer non-small cell lung cancer small cell lung cancer transformation epidermal growth factor receptor tyrosine kinase inhibitor chemotherapy drug resistance

Changes of protein expression during tumorosphere formation of small cell lung cancer circulating tumor cells

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Oncology Research 2023年第1期31卷 13-22页

作者： SANDRA STICKLER barbara rath MAXIMILIAN HOCHMAIR CLEMENS LANG LUKAS WEIGL GERHARD HAMILTON Institute of Pharmacology Medical University of ViennaViennaAustria Karl Landsteiner Institute of Lung Research and Pulmonary Oncology Klinik FloridsdorfViennaAustria Department of Trauma Surgery Sozialmedizinisches Zentrum OstDonauspitalViennaAustria Division of Special Anesthesia and Pain Medicine Medical University of ViennaViennaAustria

Small cell lung cancer(SCLC)is frequently disseminated and has a dismal prognosis with survival times of approximately two *** cancer responds well to initial chemotherapy but recurs within a short time as a globally chemoresistant *** tumor cells(CTCs)are held responsible for metastasis,the extremely high numbers of these cells in advanced SCLC allowed us to establish several permanent CTC cell *** CTCs are distinguished by the spontaneous formation of large spheroids,termed tumorospheres,in regular tissue *** contain quiescent and hypoxic cells in their interior and are associated with high chemoresistance compared to single cell *** CTC lines were compared for their expression of 84 proteins associated with cancer either as single cells or in the form of tumorospheres in Western blot *** the exception of the UHGc5 line,all other CTC lines express EpCAM and lack a complete EpCAM-negative,vimentin-positive epithelial-mesenchymal transition(EMT)*** formation of tumorospheres the expression of EpCAM,that mediates cell-cell adhesion is markedly *** such as E-Cadherin,p27 KIP1,Progranulin,BXclx,Galectin-3,and Survivin showed variable changes for the distinct CTC cell *** conclusion,EpCAM presents the most critical marker for individual SCLC CTCs and the assembly of highly chemoresistant tumorospheres.

关键词： SCLC Spheroid Chemoresistance EpCAM Topotecan Epirubicin

Protection of small-cell lung cancer circulating tumor cells by cellular fragmentation

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 345-354页

作者： barbara rath Adelina Plangger Doris Moser Maximilian Hochmair Ernst Ulsperger Gerhard Hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1190Austria Department of Cranio-Maxillofacial and Oral Surgery Medical University of ViennaVienna A-1090Austria Hospital Floridsdorf Vienna A-1210Austria Hospital Horn Horn A-3580Austria

Aim:Small-cell lung cancer(SCLC)disseminates aggressively and may exhibit high chemoresistance and poor survival *** this study,we aimed to investigate a new mechanism of drug resistance for SCLC circulating tumor cells(CTCs).Methods:SCLC CTC cell lines(n=4)which shed cellular fragments(MAT),as demonstrated by light and scanning electron microscopy,are compared to permanent SCLC *** proteins are detected by proteome arrays and the functional impact of MAT is studied using cytotoxicity tests involving cisplatin and ***:The SCLC CTC lines revealed layers of attached cellular fragments with a range of decreasing sizes from intact cells(approximately 12μm)down to small debris(approximately 2μm)which are not detectable in permanent SCLC *** SCLC CTC clusters represent cores of these fragment-coated *** profiling of MAT revealed a protein pattern similar to intact *** tests employing SCLC and SCLC CTC lines with chemotherapeutics used in therapy of SCLC demonstrated an inhibitory activity of MAT on the resulting ***:Generation of cell-associated debris by SCLC CTCs offers protective effects against cytotoxic drugs,representing a novel mechanism allowing survival of SCLC CTCs in patients.

关键词： Small cell lung cancer circulating tumor cells shedding topotecan

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

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Journal of Cancer Metastasis and Treatment 2016年第1期2卷 446-452页

作者： Gerhard Hamilton barbara rath Society for Research on Biology and Treatment of Cancer A-1160 ViennaAustria

Despite the fact that the majority of cancer patients succumb to metastatic disease,most aspects of tumor metastasis are not understood in detail at *** biologic steps of dissemination are difficult to characterize in human tumors and research is in large part confined to cell line and experimental animal ***-mesenchymal transition(EMT),intravasation of malignant cells,dissemination as circulating tumor cells(CTCs)and eventually mesenchymal-epithelial transition(MET)at distal sites are steps believed to be involved in *** cell lung cancer(SCLC)is distinguished by early dissemination and excessive numbers of CTCs,which allowed for the ex vivo expansion of six permanent CTC lines taken from relapsed *** exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large *** cells may have invaded without undergoing EMT,the role of MET is *** SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells;these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases,leading in turn to resistance and failure of *** characterization of these lines is expected to provide the markers to find the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence.

关键词： Cancer metastasis small cell lung cancer circulating tumor cells epithelial-mesenchymal transition tumorosphere chemotherapy drug resistance

Central role of altered phosphodiesterase 2-dependent signaling in the pathophysiology of cognition-based brain disorders

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Neural Regeneration Research 2025年第8期20卷 2302-2303页

作者： Asma Boulksibat Alessandra Tempio barbara Bardoni Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR7275Inserm U1323ValbonneFrance

The second messengers 3',5'-cyclic adenosine monophosphate(cAMP)and 3',5'-cyclic guanosine monophosphate(cGMP)modulate molecular pathways that are involved in a large variety of cellular *** the brain,these processes include neurogenesis,neuronal differentiation,activation and function of microglia,and synaptic plasticity,finally resulting in memory formation.

关键词： formation processes finally

Small heat shock protein B8:from cell functions to its involvement in diseases and potential therapeutic applications

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Neural Regeneration Research 2025年第10期20卷 2872-2886页

作者： Marta Chierichetti Riccardo Cristofani Valeria Crippa Veronica Ferrari Marta Cozzi Elena Casarotto Paola Pramaggiore Laura Cornaggia Guglielmo Patelli Ali Mohamed Margherita Piccolella Mariarita Galbiati Paola Rusmini barbara Tedesco Angelo Poletti Laboratory of Experimental Biology Dipartimento di Scienze Farmacologiche e Biomolecolari“Rodolfo Paoletti”(DiSFeB)Universitàdegli Studi di MilanoMilanItaly

Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock ***8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and ***8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective *** line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and *** cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under ***,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar *** note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other *** is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial *** review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its ***-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.

关键词： aggregation autophagy cancer chaperone chaperone-assisted selective autophagy cognitive impairment HSPB8 neuroinflammation neuromuscular diseases therapy

Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick Heimel Markus Kerbl LászlóGál Sylvia Nürnberger barbara Schaedl James Ferguson Nicole Swiadek Xavier Monforte Johannes C.Heinzel Antal Nógrádi Andreas H.Teuschl-Woller David Hercher Department Life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria Ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk-based nerve guidance conduit vascularization

Heterogeneous patterning of blood-brain barrier and adaptive myelination as renewing key in gray and white matter

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Neural Regeneration Research 2024年第3期19卷 481-482页

作者： barbara Pavan Department of Neuroscience and Rehabilitation University of Ferraravia L BorsariFerraraItalyCenter for Translational Neurophysiology of Speech and Communication(CTNSC)Italian Institute of Technology(IIT)via Fossato di MortaraFerraraItaly

Background:Development and homeostasis of the brain are enabled through the precise control of the cell microenvironment by the blood-brain barrier(BBB),which interfaces between the brain parenchyma and the lumen of blood microvessels,and by the blood-cerebrospinal fluid barrier,which separates the cerebrospinal fluid from the blood vessels of the choroid plexus(Villabona-Rueda et al.,2019).Here,the focus will be on the BBB,the impairment of which is considered the earliest common denominator in neurovascular diseases.

关键词： homeostasis blood