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Primary Intraocular Tumors–Molecular Mechanisms, Novel Therapeutic Strategies and Targets
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Primary Intraocular Tumors–Molecular Mechanisms, Novel Therapeutic Strategies and Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 6952

Special Issue Editors

Dr. Jacqueline Reinhard

E-Mail Website
Guest Editor
Department of Cell Morphology and Molecular Neurobiology, Ruhr-University Bochum, Bochum, Germany
Interests: chemoresistance; extracellular matrix; molecular signaling; retinoblastoma; tumor niche microenvironment; therapeutic options; tumor stem cells
Dr. Vinodh Kakkassery

E-Mail Website
Guest Editor
Department of Ophthalmology, University of Luebeck, Luebeck, Germany
Interests: chemotherapy resistance; intraocular tumors; ocular oncology; retinoblastoma; uveal melanoma; vitreoretinal lymphoma

Special Issue Information

Dear Colleagues,

Primary intraocular tumors, such as retinoblastoma, uveal melanoma, and primary vitreoretinal lymphoma, are an indescribable burden for patients by threatening sight and survival at the same time. Most likely local tumor control/metastasis prevention, eye salvage, and sight preservation are common objectives in these cancers. In order to improve the care of patients, this Special Issue invites authors to submit comprehensive molecular biological work regarding possible future improvements in diagnostics or/and therapy, displaying up-to-date knowledge and application thereof. Experts in the field will be invited to present their research, which will provide new insights into the current state of inter alia molecular patho- and signaling mechanisms, the identification of novel molecular biomarkers, and innovative targeted therapeutic options.

Dr. Jacqueline Reinhard
Dr. Vinodh Kakkassery
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Animal/cell culture models
  • Biomarker
  • Intraocular tumors
  • Molecular signaling
  • Proteomics
  • Retinoblastoma
  • Therapy approaches
  • Tumorigenesis
  • Uveal melanoma
  • Vitreoretinal lymphoma

Published Papers (3 papers)

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Research

15 pages, 2640 KiB  
Article
CXCR4, CXCR5 and CD44 May Be Involved in Homing of Lymphoma Cells into the Eye in a Patient Derived Xenograft Homing Mouse Model for Primary Vitreoretinal Lymphoma
by Neele Babst, Lisa K. Isbell, Felix Rommel, Aysegul Tura, Mahdy Ranjbar, Salvatore Grisanti, Cordula Tschuch, Julia Schueler, Soroush Doostkam, Peter C. Reinacher, Justus Duyster, Vinodh Kakkassery and Nikolas von Bubnoff
Int. J. Mol. Sci. 2022, 23(19), 11757; https://doi.org/10.3390/ijms231911757 - 04 Oct 2022
Cited by 4 | Viewed by 1624
Abstract
Background: Primary vitreoretinal lymphoma (PVRL), a rare malignancy of the eye, is strongly related to primary central nervous system lymphoma (PCNSL). We hypothesized that lymphoma cells disseminate to the CNS and eye tissue via distinct homing receptors. The objective of this study was [...] Read more.
Background: Primary vitreoretinal lymphoma (PVRL), a rare malignancy of the eye, is strongly related to primary central nervous system lymphoma (PCNSL). We hypothesized that lymphoma cells disseminate to the CNS and eye tissue via distinct homing receptors. The objective of this study was to test expression of CXCR4, CXCR5, CXCR7 and CD44 homing receptors on CD20 positive B-lymphoma cells on enucleated eyes using a PCNSL xenograft mouse model. Methods: We used indirect immunofluorescence double staining for CD20/CXCR4, CD20/CXCR5, CD20/CXCR7 and CD20/CD44 on enucleated eyes of a PCNSL xenograft mouse model with PVRL phenotype (PCNSL group) in comparison to a secondary CNS lymphoma xenograft mouse model (SCNSL group). Lymphoma infiltration was evaluated with an immunoreactive score (IRS). Results: 11/13 paired eyes of the PCNSL but none of the SCNSL group were infiltrated by CD20-positive cells. Particularly the choroid and to a lesser extent the retina of the PCNSL group were infiltrated by CD20+/CXCR4+, CD20+/CXCR5+, few CD20+/CD44+ but no CD20+/CXCR7+ cells. Expression of CXCR4 (p = 0.0205), CXCR5 (p = 0.0004) and CD44 (p < 0.0001) was significantly increased in the PCNSL compared to the SCNSL group. Conclusions: CD20+ PCNSL lymphoma cells infiltrating the eye co-express distinct homing receptors such as CXCR4 and CXCR5 in a PVRL homing mouse model. These receptors may be involved in PVRL homing into the eye. Full article
(This article belongs to the Special Issue Primary Intraocular Tumors–Molecular Mechanisms, Novel Therapeutic Strategies and Targets)
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14 pages, 2931 KiB  
Article
Protein Profiling of WERI-RB1 and Etoposide-Resistant WERI-ETOR Reveals New Insights into Topoisomerase Inhibitor Resistance in Retinoblastoma
by Vinodh Kakkassery, Timo Gemoll, Miriam M. Kraemer, Thorben Sauer, Aysegül Tura, Mahdy Ranjbar, Salvatore Grisanti, Stephanie C. Joachim, Stefan Mergler and Jacqueline Reinhard
Int. J. Mol. Sci. 2022, 23(7), 4058; https://doi.org/10.3390/ijms23074058 - 06 Apr 2022
Cited by 3 | Viewed by 2557
Abstract
Chemotherapy resistance is one of the reasons for eye loss in patients with retinoblastoma (RB). RB chemotherapy resistance has been studied in different cell culture models, such as WERI-RB1. In addition, chemotherapy-resistant RB subclones, such as the etoposide-resistant WERI-ETOR cell line have been [...] Read more.
Chemotherapy resistance is one of the reasons for eye loss in patients with retinoblastoma (RB). RB chemotherapy resistance has been studied in different cell culture models, such as WERI-RB1. In addition, chemotherapy-resistant RB subclones, such as the etoposide-resistant WERI-ETOR cell line have been established to improve the understanding of chemotherapy resistance in RB. The objective of this study was to characterize cell line models of an etoposide-sensitive WERI-RB1 and its etoposide-resistant subclone, WERI-ETOR, by proteomic analysis. Subsequently, quantitative proteomics data served for correlation analysis with known drug perturbation profiles. Methodically, WERI-RB1 and WERI-ETOR were cultured, and prepared for quantitative mass spectrometry (MS). This was carried out in a data-independent acquisition (DIA) mode. The raw SWATH (sequential window acquisition of all theoretical mass spectra) files were processed using neural networks in a library-free mode along with machine-learning algorithms. Pathway-enrichment analysis was performed using the REACTOME-pathway resource, and correlated to the molecular signature database (MSigDB) hallmark gene set collections for functional annotation. Furthermore, a drug-connectivity analysis using the L1000 database was carried out to associate the mechanism of action (MOA) for different anticancer reagents to WERI-RB1/WERI-ETOR signatures. A total of 4756 proteins were identified across all samples, showing a distinct clustering between the groups. Of these proteins, 64 were significantly altered (q < 0.05 & log2FC |>2|, 22 higher in WERI-ETOR). Pathway analysis revealed the “retinoid metabolism and transport” pathway as an enriched metabolic pathway in WERI-ETOR cells, while the “sphingolipid de novo biosynthesis” pathway was identified in the WERI-RB1 cell line. In addition, this study revealed similar protein signatures of topoisomerase inhibitors in WERI-ETOR cells as well as ATPase inhibitors, acetylcholine receptor antagonists, and vascular endothelial growth factor receptor (VEGFR) inhibitors in the WERI-RB1 cell line. In this study, WERI-RB1 and WERI-ETOR were analyzed as a cell line model for chemotherapy resistance in RB using data-independent MS. Analysis of the global proteome identified activation of “sphingolipid de novo biosynthesis” in WERI-RB1, and revealed future potential treatment options for etoposide resistance in RB. Full article
(This article belongs to the Special Issue Primary Intraocular Tumors–Molecular Mechanisms, Novel Therapeutic Strategies and Targets)
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17 pages, 3142 KiB  
Article
KIT Expression Is Regulated by DNA Methylation in Uveal Melanoma Tumors
by Viera Horvathova Kajabova, Andrea Soltysova, Lucia Demkova, Paulina Plesnikova, Darina Lyskova, Alena Furdova, Pavel Babal and Bozena Smolkova
Int. J. Mol. Sci. 2021, 22(19), 10748; https://doi.org/10.3390/ijms221910748 - 04 Oct 2021
Cited by 1 | Viewed by 1795
Abstract
Uveal melanoma (UM) is an ocular tumor with a dismal prognosis. Despite the availability of precise molecular and cytogenetic techniques, clinicopathologic features with limited accuracy are widely used to predict metastatic potential. In 51 UM tissues, we assessed a correlation between the expression [...] Read more.
Uveal melanoma (UM) is an ocular tumor with a dismal prognosis. Despite the availability of precise molecular and cytogenetic techniques, clinicopathologic features with limited accuracy are widely used to predict metastatic potential. In 51 UM tissues, we assessed a correlation between the expression of nine proteins evaluated by immunohistochemistry (IHC) (Melan-A, S100, HMB45, Cyclin D1, Ki-67, p53, KIT, BCL2, and AIFM1) and the presence of UM-specific chromosomal rearrangements measured by multiplex ligation-dependent probe amplification (MLPA), to find IHC markers with increased prognostic information. Furthermore, mRNA expression and DNA methylation values were extracted from the whole-genome data, achieved by analyzing 22 fresh frozen UM tissues. KIT positivity was associated with monosomy 3, increasing the risk of poor prognosis more than 17-fold (95% CI 1.53–198.69, p = 0.021). A strong negative correlation was identified between mRNA expression and DNA methylation values for 12 of 20 analyzed positions, five located in regulatory regions of the KIT gene (r = −0.658, p = 0.001; r = −0.662, p = 0.001; r = −0.816; p < 0.001; r = −0.689, p = 0.001; r = −0.809, p < 0.001, respectively). DNA methylation β values were also inversely associated with KIT protein expression (p = 0.001; p = 0.001; p = 0.015; p = 0.025; p = 0.002). Our findings, showing epigenetic deregulation of KIT expression, may contribute to understanding the past failure to therapeutically target KIT in UM. Full article
(This article belongs to the Special Issue Primary Intraocular Tumors–Molecular Mechanisms, Novel Therapeutic Strategies and Targets)
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