Tracing the Origins of Glioblastoma by Investigating the Role of Gliogenic and Related Neurogenic Genes/Signaling Pathways in GBM Development: A Systematic Review

Background: Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM and for this purpose it focuses primarily on developmental gliogenic processes. It also focuses on impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons.Methods:Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, astrocytogenic genes.Results:The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate specific genes to keep the cells differentiated in their specific cell type such as p300, BMP, HOPX, NRSF/REST and others. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, hey1 and others. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300 and then GFAP, leading to upregulation of nestin, SHH, NF-κB and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. Conclusion: Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, ASCL1 and others. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR and others.

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe the generation of a collection of pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight weeks, indicating the feasibility of personalized drug screening. Molecular, genetic and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to six months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

Expression of pluripotency-related genes in human glioblastoma

Background Cancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2 and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy. Methods The expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2 and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM). Results and Conclusion The results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.

Squamous Differentiation in the Thyroid: Metaplasia, Neoplasia, or Bystander?

Background. Squamous differentiation within the thyroid is seen in a variety of settings. Squamous epithelium is non-native to the thyroid, and its debated origins span reactive metaplasia and developmental/embryologic remnants. Despite a lack of clarity as to its evolution, squamous epithelium may be associated with both neoplastic and non-neoplastic processes. Methods. Thyroid pathology reports spanning a 30-year period were reviewed for terms indicating squamous features. Associated diagnostic and clinical information was collated. Results. Four hundred and twenty seven of 17,452 (2.4%) thyroid surgical pathology cases during this period utilized terminology indicating squamous differentiation including 243 malignant (58%) and 178 benign (42%) diagnoses. There were 111 (26%) primary thyroid malignancies with squamous differentiation, 116 (28%) malignancies of non-thyroid origin including local extension from nearby cancers, and 16 (4%) malignancies of uncertain primary. Most benign lesions were non-neoplastic (84%). The minor subset representing benign neoplasia was interpreted as secondary reactive changes. Conclusion. While squamous differentiation is seen routinely in the thyroid, it is most commonly reported in malignancy. For primary thyroid malignancies reported to demonstrate a squamous component, biologically aggressive tumors were overrepresented. Available evidence suggests that multiple pathways may contribute to the presence of squamous epithelium in the thyroid including metaplasia of mature follicular cells, development from established embryonic remnants, or inception in putative, incompletely characterized stem-like cells. Our retrospective review presents an institutional landscape from which further investigation into the frequency and unique histologic and molecular context of intrathyroidal squamous differentiation as a driver or terminal event in thyroid pathophysiology.

Leiomyosarcoma of urinary bladder with unusual recurrence in intestinal mucosa and peritoneum: a case report

Background Leiomyosarcomas of urinary bladder constitute rare malignant sarcomas with very few cases reported in literature. Case presentation Here, we present a case of bladder leiomyosarcoma in a well-preserved female. She failed to respond to standard chemotherapy and had a rapidly downhill course with unusual metastases in anastomotic site and peritoneum soon after surgery. Despite multimodality management including resection of primary and metastatic site, systemic therapy and pelvic radiotherapy, our patient had dismal prognosis with an overall survival of 1.7 years. Conclusion Leiomyosarcomas of bladder are aggressive tumors and have a very poor prognosis; thus, future research should focus on optimizing more effective treatment regimes.

PPM1D Is a Therapeutic Target in Childhood Neural Tumors

Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers.

MALIGNANT PROLIFERATING TRICHILEMMAL TUMOR ONE CASE AND LITERATURE REVIEW

Proliferating trichilemmal tumors (PTTs) are uncommon lesions. PTT is thought to originate from the trichilemmal cyst (TC) and have the potential for malignant transformation, at which point it is termed a malignant proliferating trichilemmal tumor (MPTT). we report an observation of a 55-year-old lady patient presenting with a malignant proliferative trichilemmal tumor, emphasizing the aggressive, rapidly extensible and metastatic character. MPTTare aggressive tumors with a bad prognosis, the treatment of which is based on surgery with margins of 1 cm, lymph node dissection in the event of lymph node involvement and radio-chemotherapy.

Radioresistance in Prostate Cancer: Focus on the Interplay between NF-κB and SOD

Prostate cancer occurs frequently in men and can often lead to death. Many cancers, including prostate cancer, can be initiated by oxidative insult caused by free radicals and reactive oxygen species. The superoxide dismutase family removes the oxygen-derived reactive oxygen species, and increased superoxide dismutase activity can often be protective against prostate cancer. Prostate cancer can be treated in a variety of ways, including surgery, androgen deprivation therapy, radiation therapy, and chemotherapy. The clinical trajectory of prostate cancer varies from patient to patient, but more aggressive tumors often tend to be radioresistant. This is often due to the free-radical and reactive-oxygen-species-neutralizing effects of the superoxide dismutase family. Superoxide dismutase 2, which is especially important in this regard, can be induced by the NF-κB pathway, which is an important mechanism in radioresistance. This information has enabled the development of interventions that manipulate the NF-κB mechanism to treat prostate cancer.

Cilium Expression Score Predicts Glioma Survival

The accurate classification, prognostication, and treatment of gliomas has been hindered by an existing cellular, genomic, and transcriptomic heterogeneity within individual tumors and their microenvironments. Traditional clustering is limited in its ability to distinguish heterogeneity in gliomas because the clusters are required to be exclusive and exhaustive. In contrast, biclustering can identify groups of co-regulated genes with respect to a subset of samples and vice versa. In this study, we analyzed 1,798 normal and tumor brain samples using an unsupervised biclustering approach. We identified co-regulated gene expression profiles that were linked to proximally located brain regions and detected upregulated genes in subsets of gliomas, associated with their histologic grade and clinical outcome. In particular, we present a cilium-associated signature that when upregulated in tumors is predictive of poor survival. We also introduce a risk score based on expression of 12 cilium-associated genes which is reproducibly informative of survival independent of other prognostic biomarkers. These results highlight the role of cilia in development and progression of gliomas and suggest potential therapeutic vulnerabilities for these highly aggressive tumors.

Utility of Three-Protein Panels in the Separation of Aggressive Prostate Cancer from Non-Aggressive Tumors

Background Prostate cancer (PCa) is a heterogeneous group of tumors, including non-aggressive (NAG) and aggressive (AG) subtypes, with variable clinical outcomes. We assessed the diagnostic utility of selected protein markers to identify AG tumors. Methods The TMA was constructed, including NAG and AG. 12 protein markers were evaluated using the TMA by IHC stains. The makers were also evaluated for their potential utility as single or panels for distinguishing AG from NAG tumors. Results The higher expressions of four protein markers, including prostate specific membrane antigen (PSMA), phospho-EGFR, androgen receptor (AR), and P16, were identified in AG tumors of Gleason score 4 and 5. In contrast, Galectin-3, DPP4 and MAN1B1 revealed stronger staining patterns in NAG tumors. Sensitivity and specificity of individual marker varied widely. In tow-marker panels, especially in the panel of DPP4 and PSMA, the specificity was 38.46% at 95% sensitivity. To further improve the detection ability, we combined DPP4 and PSMA with either Galectin-3 or phospho-EGFR into three-marker panels. The specificity achieved >46% at 95% sensitivity and AUC was >0.85. Conclusions Our panels can be used to improve the separation of AG from NAG tumor and to add in the optimization of the treatment strategy for patients.