Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an “immune-cold” tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.

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Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

10.21203/rs.3.rs-33369/v1 ◽

2020 ◽

Author(s):

Qiaoyun Zhao ◽

Rulin Zhao ◽

Conghua Song ◽

Huan Wang ◽

Jianfang Rong ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Poor Prognosis ◽

Bioinformatics Analysis ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Coexpressed Genes

Abstract Background Insulin-like growth factor binding protein-7 (IGFBP7) contributes to multiple biological processes in various tumors. However, the role of IGFBP7 in gastric cancer (GC) is still undetermined. The study aims to explore the role of IGFBP7 in GC via an integrated bioinformatics analysis.Methods IGFBP7 expression levels in GC and its normal gastric tissues were analyzed using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The methylation analysis was conducted with MEXPRESS, UALCAN and Xena online tools. The survival analysis was conducted using the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Coexpressed genes of IGFBP7 were selected with the cBioPortal tool and enrichment analysis was conducted with the clusterProfiler package in R software. Gene set enrichment analysis (GSEA) was performed to explore the IGFBP7-related biological processes involved in GC. Correlations between IGFBP7 and immune cell infiltrates were analyzed using the TIMER database.Results IGFBP7 expression was significantly upregulated in GC and correlated with stage, grade, tumor status and Helicobacter pylori infection. High IGFBP7 expression and low IGFBP7 methylation levels were significantly associated with short survival of patients with GC. Univariate and multivariate analyses revealed that IGFBP7 was an independent risk factor for GC. The coexpressed genes LHFPL6, SEPTIN4, HSPB2, LAYN and GGT5 predicted unfavorable outcomes of GC. Enrichment analysis showed that the coexpressed genes were involved in extracellular matrix (ECM)-related processes. GSEA indicated that IGFBP7 was positively related to ECM and inflammation-related pathways. TIMER analysis indicated that the IGFBP7 expression level was strongly correlated with genes related to various infiltrating immune cells in GC, especially with gene markers of tumor associated macrophages (TAMs).Conclusions We demonstrate that increased IGFBP7 expression correlates with poor prognosis and immune cell infiltration in GC. IGFBP7 might be a potential biomarker for the diagnosis and targeted therapy for GC.

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High PRMT6 expression Associated With Prognosis and Immune Infiltration in Glioma

10.21203/rs.3.rs-210553/v1 ◽

2021 ◽

Author(s):

Yi Yang ◽

Zhenshuang Wang ◽

Shengrong Long ◽

Jinhai Huang ◽

Chengran Xu ◽

...

Keyword(s):

Risk Factor ◽

Poor Prognosis ◽

Enrichment Analysis ◽

Arginine Methyltransferase ◽

Clinical Indicators ◽

Immune Infiltration ◽

Tumor Tissues ◽

Potential Biomarker ◽

The Relationship

Abstract Background Glioma is characterised by easy invasion of surrounding tissues, high mortality and poor prognosis. Moreover, the prognosis of glioma is getting worse and worse with the increase of grade, which is not optimistic. Therefore, biological markers for glioma are needed in clinical to detect and evaluate the situation and prognosis of patients with glioma. In many studies, we have found that the protein arginine methyltransferase 6 (PRMT6) expression is elevated in various tumors, which is associated with prognosis of patient. However, there has been no report or study on the role of PRMT6 in glioma. Methods In this study, we used various tumor-related databases to analyze the mechanism of PRMT6 in tumors, especially gliomas, from bioinformatics, and carried out relevant experimental verification with tumor tissues extracted from patients during surgery. Besides, we analyzed the relationship between PRMT6 expression and immune infiltration and immune-related cells, and discussed the possible mechanisms. We also discussed the role of PRMT6 expression in glioma from mutation, clinical indicators, enrichment analysis, and immunohistochemical results. Results PRMT6 is significantly differentially expressed in multiple tumors, which is associated with survival and prognosis. Especially in gliomas, the PRMT6 expression gradually increased with the grade increasing. Besides, PRMT6 can be used as an independent prognostic risk factor in the nomogram and has been verified in various databases. Conclusions Our results indicate that high PRMT6 expression is a potential biomarker for predicting prognosis and progression of glioma.

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Multifaceted Functional Role of Semaphorins in Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms20092144 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2144 ◽

Cited By ~ 3

Author(s):

Cristiana Angelucci ◽

Gina Lama ◽

Gigliola Sica

Keyword(s):

Axon Guidance ◽

Treatment Options ◽

Migration And Invasion ◽

Tumor Type ◽

Metastatic Progression ◽

Oncogenic Pathways ◽

Membrane Bound ◽

Wide Group

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent trials based on the molecular targeting of some of the GBM hallmark pathways (e.g., angiogenesis) have not produced any significant improvement in overall survival. The urgent need to develop more efficacious targeted therapies has led to a better molecular characterization of GBM, revealing an emerging role of semaphorins in GBM progression. Semphorins are a wide group of membrane-bound and secreted proteins, originally identified as axon guidance cues, signaling through their receptors, neuropilins, and plexins. A number of semaphorin signals involved in the control of axonal growth and navigation during development have been found to furthermore participate in crosstalk with different dysfunctional GBM pathways, controlling tumor cell proliferation, migration, and invasion, as well as tumor angiogenesis or immune response. In this review, we summarize the regulatory activities mediated by semaphorins and their receptors on the oncogenic pathways implicated in GBM growth and invasive/metastatic progression.

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Fibronectin in Cancer: Friend or Foe

Cells ◽

10.3390/cells9010027 ◽

2019 ◽

Vol 9 (1) ◽

pp. 27 ◽

Cited By ~ 17

Author(s):

Tsung-Cheng Lin ◽

Cheng-Han Yang ◽

Li-Hsin Cheng ◽

Wen-Tsan Chang ◽

Yuh-Rong Lin ◽

...

Keyword(s):

Tumor Progression ◽

Poor Prognosis ◽

Therapeutic Strategies ◽

Malignant Progression ◽

Metastatic Progression ◽

Future Perspectives ◽

Tumor Microenvironments ◽

Tumor Transformation

The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.

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MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

International Journal of Molecular Sciences ◽

10.3390/ijms21165648 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5648

Author(s):

Karen Aughton ◽

Helen Kalirai ◽

Sarah E. Coupland

Keyword(s):

Uveal Melanoma ◽

Primary Tumour ◽

Treatment Options ◽

Protein Translation ◽

Rare Tumour ◽

Rna Molecules ◽

Signalling Molecules ◽

Clinical Biomarkers ◽

Disseminated Disease

Uveal melanoma (UM) is a rare tumour of the eye, characterised by a high propensity to metastasise in half of all patients, most frequently to the liver. Although there are effective treatment options for the primary tumour, once metastasis has occurred prognosis is poor, with overall survival limited to months. Currently, there are no effective treatments for metastatic UM, despite the tumour having a well-defined signalling pathway to which many therapies have been directed. In an effort to develop novel treatment approaches, understanding the role of other signalling molecules, such as microRNAs, is fundamental. MicroRNAs (miRNAs) are small non-coding RNA molecules involved in posttranscriptional gene regulation, resulting in reduced target gene expression and subsequent protein translation. In UM, several dysregulated miRNAs have been proposed to play a functional role in disease progression, whereas others have been put forward as clinical biomarkers of high-risk disease following isolation from blood, plasma and exosomes. Most recently, analyses of large datasets have identified promising prognostic miRNA signatures and panels. This review navigates the plethora of aberrant miRNAs disclosed so far in UM, and maps these to signalling pathways, which could be targeted in future therapies for the disseminated disease.

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Overexpression of GINS4 is associated with poor prognosis and survival in glioma patients

Molecular Medicine ◽

10.1186/s10020-021-00378-0 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Binfeng Liu ◽

Zhendong Liu ◽

Yanbiao Wang ◽

Xiaoyu Lian ◽

Zhibin Han ◽

...

Keyword(s):

Prognostic Factor ◽

Clinical Features ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Enrichment Analysis ◽

Independent Prognostic Factor ◽

Vast Number ◽

Close Relationship

Abstract Background GINS4, an indispensable component of the GINS complex, is vital for a variety of cancer. However, no known empirical research has focused on exploring relationships between GINS4 and glioma. Thus, this study aims to understand and explain the role of GINS4 in glioma. Method First, we used the data in the CGGA, TCGA, GEO, GEPIA, and HPA databases to explore the expression level of GINS4 in glioma, the correlation between GINS4 expression and the clinical features of glioma, its impact on the survival of glioma patients, and verified the analysis results through RT-qPCR, IHC, and meta-analysis. Subsequently, GSEA enrichment analysis is used to find the potential molecular mechanism of GINS4 to promote the malignant process of glioma and the anti-glioma drugs that may target GINS4 screened by CMap analysis. Moreover, we further explored the influence of the GINS4 expression on the immune microenvironment of glioma patients through the TIMER database. Results Our results suggested that GINS4 was elevated in glioma, and the overexpression of GINS4 was connected with a vast number of clinical features. The next, GINS4 as an independent prognostic factor, which can result in an unfavorable prognosis of glioma. Once more, GINS4 may be participating in the oncogenesis of glioma through JAK-STAT signaling pathways, etc. 6-thioguanine, Doxazosin, and Emetine had potential value in the clinical application of drugs targeting GINS4. Finally, the expression exhibited a close relationship with some immune cells, especially Dendritic cells. Conclusion GINS4 is an independent prognostic factor that led to a poor prognosis of glioma. The present study revealed the probable underlying molecular mechanisms of GINS4 in glioma and provided a potential target for improving the prognosis of glioma.

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Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD)

Frontiers in Oncology ◽

10.3389/fonc.2021.800053 ◽

2022 ◽

Vol 11 ◽

Author(s):

Sherise D. Ferguson ◽

Elena I. Fomchenko ◽

Renato A. Guerrieri ◽

Isabella C. Glitza Oliva

Keyword(s):

Poor Prognosis ◽

Treatment Options ◽

Circulating Tumor Dna ◽

Diagnosis And Treatment ◽

Leptomeningeal Disease ◽

Survival Times ◽

Aggressive Therapy ◽

Treatment Prognosis ◽

Tumor Dna

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

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Construction and Validation of a Novel Pyroptosis-Related Gene Signature to Predict the Prognosis of Uveal Melanoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761350 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuan Cao ◽

Jiaheng Xie ◽

Liang Chen ◽

Yiming Hu ◽

Leili Zhai ◽

...

Keyword(s):

Uveal Melanoma ◽

Poor Prognosis ◽

Tumor Recurrence ◽

Gene Signature ◽

Related Gene ◽

Programmed Death ◽

Prognosis Model ◽

New Ideas ◽

Full Throttle

Uveal melanoma is the most common primary intraocular tumor with a poor prognosis. Currently, treatment for UVM is limited, and the development of drug resistance and tumor recurrence are common. Therefore, it is important to identify new prognostic biomarkers of UVM and explore their role in the tumor microenvironment. Pyroptosis is a way of cell programmed death, and related research is in full throttle. However, the role of pyroptosis in UVM is unclear. In this study, we constructed the prognosis model of pyroptosis-related genes of UVM. This model can accurately guide the prognosis of UVM, and different groups differ in immune infiltration. We further verified our results in cell experiments. To some extent, our study can provide new ideas for the diagnosis and treatment of UVM.

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Extracellular matrix: the gatekeeper of tumor angiogenesis

Biochemical Society Transactions ◽

10.1042/bst20190653 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1543-1555 ◽

Cited By ~ 10

Author(s):

Maurizio Mongiat ◽

Simone Buraschi ◽

Eva Andreuzzi ◽

Thomas Neill ◽

Renato V. Iozzo

Keyword(s):

Extracellular Matrix ◽

Tumor Angiogenesis ◽

Signaling Cascades ◽

Cancer Growth ◽

Cell Behavior ◽

Metastatic Progression ◽

Surface Receptors ◽

The Matrix ◽

Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

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