scholarly journals Atypical localization of Eph-RTKs in childhood cancer rhabdomyosarcoma

2019 ◽  
Author(s):  
◽  
Ronnie Marie LaCombe
Keyword(s):  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Eph Receptors ◽  
Primary Tumors ◽  
Eph Receptor ◽  
First Case ◽  
Tumor Types

Rhabdomyosarcoma (RMS), the most common soft tissue tumor in children, is an aggressive cancer with a 5-year survival rate of 24% if it has metastasized. Current treatment options are limited to surgery, chemotherapy and radiation, so there is a significant unmet need for targeted therapies. Eph receptor tyrosine kinases have been implicated in the development and progression of many other tumor types. Recent results from our group identified several Eph receptors expressed by primary muscle stem cells (satellite cells), which led us to screen for protein expression of Ephs in canine RMS primary tumors as well as mouse and human RMS cell lines. Intriguingly, we noted strong expression but abnormal localization of one Eph receptor: in multiple tumors from all three species, we detected EphA1 in the nucleus of interphase cells. Mislocalization of RTKs to the nucleus in other tumor types has been shown to promote cancer progression, with the classic case being ErbBs. There are only two published studies about Ephs localizing to the nucleus and to date no other nuclear RTKs have been identified in RMS. These data represent the first case of a nuclear RTK in RMS, and the first time that EphA1 has been detected in the nucleus of any cell type.

scholarly journals Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 692 ◽  
Author(s):  
Elisabete Cruz da Silva ◽  
Monique Dontenwill ◽  
Laurence Choulier ◽  
Maxime Lehmann
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Cancer Cell Proliferation ◽  
Remarkable Feature ◽  
Rtk Signaling ◽  
Intracellular Signal ◽  
New Treatment

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.

scholarly journals The Shb scaffold binds the Nck adaptor protein, p120 RasGAP, and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2

2020 ◽  
Vol 295 (12) ◽  
pp. 3932-3944 ◽  
Author(s):  
Melany J. Wagner ◽  
Marilyn S. Hsiung ◽  
Gerald D. Gish ◽  
Rick D. Bagshaw ◽  
Sasha A. Doodnauth ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cell Movement ◽  
Adaptor Protein ◽  
Receptor Activation ◽  
Sh2 Domain ◽  
Tumor Formation ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Varied Composition ◽  
Cell Segregation

Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)–mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain–containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2–ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.

scholarly journals Chronic Constipation: Current Management and Challenges

2011 ◽  
Vol 25 (suppl b) ◽  
pp. 5B-6B ◽  
Author(s):  
Martin Storr
Keyword(s):  
Canadian Journal ◽  
Chronic Constipation ◽  
Initial Treatment ◽  
Unmet Needs ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Current Management ◽  
Novel Drugs ◽  
Canadian Market

Many challenges are associated with the diagnosis and management of patients with chronic constipation. Some of these challenges arise from the currently incomplete understanding of what causes constipation and from the difficulties in diagnosing and classifying the heterogeneous group of patients with chronic constipation. Despite the availability of different treatment options for constipation, an unmet need for drugs in the treatment of patients with chronic constipation remains. This holds especially true for patients who fail an initial treatment. With promising novel drugs either close to approval for the Canadian market or on the horizon, many of these unmet needs may be addressed. The present supplement toThe Canadian Journal of Gastroenterologyprovides an educational overview of the current understanding of the diagnosis, epidemiology, pathophysiology and management of chronic constipation, and summarizes current treatment options in light of current and newly available drugs.

scholarly journals Inflammasomes and Proteostasis Novel Molecular Mechanisms Associated With Atrial Fibrillation

2020 ◽  
Vol 127 (1) ◽  
pp. 73-90 ◽  
Author(s):  
Na Li ◽  
Bianca J.J.M. Brundel
Keyword(s):  
Atrial Fibrillation ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Cytoskeletal Proteins ◽  
Age Related ◽  
Research Findings ◽  
Shock Proteins

Atrial fibrillation (AF), the most common progressive and age-related cardiac arrhythmia, affects millions of people worldwide. AF is associated with common risk factors, including hypertension, diabetes mellitus, and obesity, and serious complications such as stroke and heart failure. Notably, AF is progressive in nature, and because current treatment options are mainly symptomatic, they have only a moderate effect on prevention of arrhythmia progression. Hereto, there is an urgent unmet need to develop mechanistic treatments directed at root causes of AF. Recent research findings indicate a key role for inflammasomes and derailed proteostasis as root causes of AF. Here, we elaborate on the molecular mechanisms of these 2 emerging key pathways driving the pathogenesis of AF. First the role of NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome on AF pathogenesis and cardiomyocyte remodeling is discussed. Then we highlight pathways of proteostasis derailment, including exhaustion of cardioprotective heat shock proteins, disruption of cytoskeletal proteins via histone deacetylases, and the recently discovered DNA damage-induced nicotinamide adenine dinucleotide + depletion to underlie AF. Moreover, potential interactions between the inflammasomes and proteostasis pathways are discussed and possible therapeutic targets within these pathways indicated.

scholarly journals Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis

2019 ◽  
Vol 20 (19) ◽  
pp. 4799 ◽  
Author(s):  
Zuzanna Nowicka ◽  
Konrad Stawiski ◽  
Bartłomiej Tomasik ◽  
Wojciech Fendler
Keyword(s):  
Head And Neck ◽  
Cancer Progression ◽  
Treatment Options ◽  
Survival Rates ◽  
Chemotherapy Resistance ◽  
Second Primary ◽  
Special Focus ◽  
Primary Tumors ◽  
Extracellular Mirnas ◽  
Extracellular Mirna

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences and second primary tumors remain a great challenge for the clinicians. Presently, there is no biomarker for patient surveillance that could help identify patients with HNSCC that are more likely to experience a relapse or early progression, potentially requiring closer follow-up or salvage treatment. MicoRNAs (miRNAs) are non-coding RNA molecules that posttranscriptionally modulate gene expression. They are highly stable and their level can be measured in biofluids including serum, plasma, and saliva, enabling quick results and allowing for repeated analysis during and after the completion of therapy. This has cemented the role of miRNAs as biomarkers with a huge potential in oncology. Since altered miRNA expression was described in HNSCC and many miRNAs play a role in radio- and chemotherapy resistance, cancer progression, and metastasis, they can be utilized as biomarkers of these phenomena. This review outlines recent discoveries in the field of extracellular miRNA-based biomarkers of HNSCC progression and metastasis, with a special focus on HPV-related cancers and radioresistance.

Dancing with the dead: Eph receptors and their kinase-null partnersThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 115-129 ◽  
Author(s):  
Luke Truitt ◽  
Andrew Freywald
Keyword(s):  
Membrane Proteins ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Receptor Tyrosine Kinases ◽  
Peer Review Process ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Biological Responses ◽  
Wide Range ◽  
Multicellular Organisms

Eph receptor tyrosine kinases and their ligands, ephrins, are membrane proteins coordinating a wide range of biological functions both in developing embryos and in adult multicellular organisms. Numerous studies have implicated Eph receptors in the induction of opposing responses, including cell adhesion or repulsion, support or inhibition of cell proliferation and cell migration, and progression or suppression of multiple malignancies. Similar to other receptor tyrosine kinases, Eph receptors rely on their ability to catalyze tyrosine phosphorylation for signal transduction. Interestingly, however, Eph receptors also actively utilize three kinase-deficient receptor tyrosine kinases, EphB6, EphA10, and Ryk, in their signaling network. The accumulating evidence suggests that the unusual flexibility of the Eph family, allowing it to initiate antagonistic responses, might be partially explained by the influence of the kinase-dead participants and that the exact outcome of an Eph-mediated action is likely to be defined by the balance between the signaling of catalytically potent and catalytically null receptors. We discuss in this minireview the emerging functions of the kinase-dead EphB6, EphA10, and Ryk receptors both in normal biological responses and in malignancy, and analyze currently available information related to the molecular mechanisms of their action in the context of the Eph family.

scholarly journals Chronic Constipation: Current Management and Challenges

2011 ◽  
Vol 25 (suppl b) ◽  
pp. 5B-6B
Author(s):  
Martin Storr
Keyword(s):  
Canadian Journal ◽  
Chronic Constipation ◽  
Initial Treatment ◽  
Unmet Needs ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Current Management ◽  
Novel Drugs ◽  
Canadian Market

Many challenges are associated with the diagnosis and management of patients with chronic constipation. Some of these challenges arise from the currently incomplete understanding of what causes constipation and from the difficulties in diagnosing and classifying the heterogeneous group of patients with chronic constipation. Despite the availability of different treatment options for constipation, an unmet need for drugs in the treatment of patients with chronic constipation remains. This holds especially true for patients who fail an initial treatment. With promising novel drugs either close to approval for the Canadian market or on the horizon, many of these unmet needs may be addressed. The present supplement toThe Canadian Journal of Gastroenterologyprovides an educational overview of the current understanding of the diagnosis, epidemiology, pathophysiology and management of chronic constipation, and summarizes current treatment options in light of current and newly available drugs.

Eph receptors and ephrins: effectors of morphogenesis

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2033-2044 ◽  
Author(s):  
N. Holder ◽  
R. Klein
Keyword(s):  
Cell Migration ◽  
Pattern Formation ◽  
Axon Guidance ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Structural Domains ◽  
Eph Receptor

Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.

scholarly journals Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Lisa E. S. Crose ◽  
Corinne M. Linardic
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Soft Tissue Sarcomas ◽  
Risk Groups ◽  
Current Treatment ◽  
Childhood And Adolescence ◽  
Surface Receptors ◽  
Genetic Abnormalities ◽  
Blocking Antibodies

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS.

scholarly journals Streptococcus pyogenes aortic aneurysm infection: forgotten but not gone

2013 ◽  
Vol 5 (2) ◽  
pp. 11 ◽  
Author(s):  
Bradley J. Gardiner ◽  
Joy Wong ◽  
Ming Yii ◽  
Timothy Buckenham ◽  
Tony M. Korman
Keyword(s):  
Aortic Aneurysm ◽  
Streptococcus Pyogenes ◽  
Treatment Options ◽  
Current Treatment ◽  
Common Cause ◽  
Endoluminal Repair ◽  
First Case ◽  
Infected Aortic Aneurysm

Historically, <em>Streptococcus pyogenes</em> was a common cause of endocarditis and infected aortic aneurysm. Today, endovascular infections due to this organism have become exceedingly rare. We report the first case of aortic aneurysm infection due to <em>S. pyogenes </em>treated with initial endoluminal repair, review previous reports and discuss current treatment options.

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