scholarly journals VEGFR-2 Expression in Glioblastoma Multiforme Depends on Inflammatory Tumor Microenvironment

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jana Jaal ◽  
Marju Kase ◽  
Ave Minajeva ◽  
Mikk Saretok ◽  
Aidi Adamson ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Optical Density ◽  
Antiangiogenic Therapy ◽  
Growth Factor Receptor ◽  
Positive Association ◽  
Staining Intensity ◽  
Tissue Expression ◽  
The Impact

Glioblastoma multiforme (GBM) is one of the most angiogenic tumors. However, antiangiogenic therapy has not shown significant clinical efficacy. The aim of our study was to evaluate the impact of inflammatory tumor microenvironment on the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). Surgically excised primary GBM tissues were histologically examined for overall extent of inflammation (score 1–3). After immunohistochemistry, the tissue expression of ICAM-1 (optical density), the number of VEGFR-2 positive (VEGFR-2+) blood vessels (per microscopic field), and the endothelial staining intensity of VEGFR-2 (score 0–3) were determined. In GBM, the extent of inflammation was 1.9 ± 0.7 (group mean ± SD). Mean optical density of inflammatory mediator ICAM-1 was 57.0 ± 27.1 (pixel values). The number of VEGFR-2+ blood vessels and endothelial VEGFR-2 staining intensity were 6.2 ± 2.4 and 1.2 ± 0.8, respectively. A positive association was found between endothelial VEGFR-2 staining intensity and the extent of inflammation (p=0.005). Moreover, VEGFR-2 staining intensity correlated with the expression level of ICAM-1 (p=0.026). The expression of VEGFR-2, one of the main targets of antiangiogenic therapy, depends on GBM microenvironment. Higher endothelial VEGFR-2 levels were seen in the presence of more pronounced inflammation. Target dependence on inflammatory tumor microenvironment has to be taken into consideration when treatment approaches that block VEGFR-2 signaling are designed.

scholarly journals A New Antitumor Direction: Tumor-Specific Endothelial Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Liang ◽  
Shouqi Wang ◽  
Guowei Zhang ◽  
Baoyu He ◽  
Qingli Bie ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Side Effects ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Antiangiogenic Therapy ◽  
Clinical Effects ◽  
Antiangiogenic Drugs ◽  
Tumor Blood Vessels ◽  
New Treatment

Targeting tumor blood vessels is an important strategy for tumor therapies. At present, antiangiogenic drugs are known to have significant clinical effects, but severe drug resistance and side effects also occur. Therefore, new specific targets for tumor and new treatment methods must be developed. Tumor-specific endothelial cells (TECs) are the main targets of antiangiogenic therapy. This review summarizes the differences between TECs and normal endothelial cells, assesses the heterogeneity of TECs, compares tumorigenesis and development between TECs and normal endothelial cells, and explains the interaction between TECs and the tumor microenvironment. A full and in-depth understanding of TECs may provide new insights for specific antitumor angiogenesis therapies.

scholarly journals Comprehensive Analysis of VEGFR2 Expression in HPV-Positive and -Negative OPSCC Reveals Differing VEGFR2 Expression Patterns

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5221
Author(s):  
Senem Uzun ◽  
Yüksel Korkmaz ◽  
Nora Wuerdemann ◽  
Christoph Arolt ◽  
Behrus Puladi ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Tumor Cells ◽  
Expression Patterns ◽  
Growth Factor Receptor ◽  
Decisive Role ◽  
Hpv Infection ◽  
Stem Cell Markers ◽  
Autocrine Loop ◽  
Hpv Status ◽  
The Impact

VEGF signaling regulated by the vascular endothelial growth factor receptor 2 (VEGFR2) plays a decisive role in tumor angiogenesis, initiation and progression in several tumors including HNSCC. However, the impact of HPV-status on the expression of VEGFR2 in OPSCC has not yet been investigated, although HPV oncoproteins E6 and E7 induce VEGF-expression. In a series of 56 OPSCC with known HPV-status, VEGFR2 expression patterns were analyzed both in blood vessels from tumor-free and tumor-containing regions and within tumor cells by immunohistochemistry using densitometry. Differences in subcellular colocalization of VEGFR2 with endothelial, tumor and stem cell markers were determined by double-immunofluorescence imaging. Immunohistochemical results were correlated with clinicopathological data. HPV-infection induces significant downregulation of VEGFR2 in cancer cells compared to HPV-negative tumor cells (p = 0.012). However, with respect to blood vessel supply, the intensity of VEGFR2 staining differed only in HPV-positive OPSCC and was upregulated in the blood vessels of tumor-containing regions (p < 0.0001). These results may suggest different routes of VEGFR2 signaling depending on the HPV-status of the OPSCC. While in HPV-positive OPSCC, VEGFR2 might be associated with increased angiogenesis, in HPV-negative tumors, an autocrine loop might regulate tumor cell survival and invasion.

Quantifying the impact of antiangiogenic therapy on hypoxia and implications for radiation therapy in glioblastoma multiforme with a biomathematical model.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13028-e13028
Author(s):  
Andrea Hawkins-Daarud ◽  
Russell Rockne ◽  
Paul Kinahan ◽  
Mark Muzi ◽  
Adam Alessio ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Glioblastoma Multiforme ◽  
Antiangiogenic Therapy ◽  
Specific Treatment ◽  
Patient Specific ◽  
Optimal Timing ◽  
Angiogenic Therapy ◽  
Wide Range ◽  
Simulation Results ◽  
The Impact

e13028 Background: Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. As angiogenesis is a major hallmark of GBM, it can be inferred that hypoxia plays a prominent role in the progression of the disease. However, due to difficulty in assessing hypoxia, the development and evolution of hypoxia has not been well studied for GBM. 18F-Fluoromisonidazole (FMISO) PET indirectly measures hypoxia. It is known that hypoxia reduces the efficacy of radiation therapy, and one current strategy being explored is to combine anti-angiogenic therapy and radiation therapy. However, it is unclear whether anti-angiogenic therapy is ultimately reducing or increasing hypoxia nor is it clear how long the effects last. Methods: We have developed a spatio-temporal biomathematical model for glioma proliferation and invasion that incorporates the angiogenic cascade. In this context, we can simulate the action of anti-angiogenic treatment, such as bevacizumab, by modifying the availability of angiogenic factors. By applying a pharmacokinetic model for the uptake of FMISO to the simulation results, we can generate the corresponding FMISO-PET images during and after anti-angiogenic therapy to compare with what would be seen in the clinic. Results: Simulation results for a wide range of tumor kinetics demonstrated that hypoxia in general decreased during anti-angiogenic therapy. However, the rates at which it decreased and the time for the hypoxia to return to pre-treatment levels were not uniform. Conclusions: Dynamic understanding of anti-angiogenic therapy effects on vascular normalization and hypoxia suggest that optimal timing of radiation therapy and anti-angiogenic therapies would vary by patient. This biomathematical model can be tuned to individual patients’ tumors and provide similar information as a FMISO-PET image and also give insight into the dynamics of the hypoxia over time. Such insight could be invaluable to patient-specific treatment planning for combining radiation with antiangiogenics.

scholarly journals Impact of Blood Vessel Quantity and Vascular Expression of CD133 and ICAM-1 on Survival of Glioblastoma Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Ave Minajeva ◽  
Marju Kase ◽  
Mikk Saretok ◽  
Aidi Adamson-Raieste ◽  
Sandra Kase ◽  
...  
Keyword(s):  
Overall Survival ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Median Survival ◽  
Antiangiogenic Therapy ◽  
Staining Intensity ◽  
Survival Times ◽  
Microvascular Proliferation ◽  
High Median ◽  
Vascular Expression

Glioblastoma (GB) is the most angiogenic tumor. Nevertheless, antiangiogenic therapy has not shown significant clinical efficacy. The aim of this study was to assess blood vessel characteristics on survival of GB patients. Surgically excised GB tissues were histologically examined for overall proportion of glomeruloid microvascular proliferation (MP) and the total number of blood vessels. Also, immunohistochemical vascular staining intensities of CD133 and ICAM-1 were determined. Vessel parameters were correlated with patients’ overall survival. The survival time depended on the number of blood vessels (p=0.03) but not on the proportion of MP. Median survival times for patients with low (<median) and high (≥median) number of blood vessels were 9.0 months (95% CI: 7.5–10.5) and 12.0 months (95% CI: 9.3–14.7). Also, median survival times for patients with low (<median) and high (≥median) vascular expression level of CD133 were 9.0 months (95% CI: 8.0–10.1) and 12.0 months (95% CI: 10.3–13.7). In contrast, the staining intensity of vascular ICAM-1 did not affect survival. In multivariate analysis, the number of blood vessels emerged as an independent predictor for longer overall survival (HR: 2.4, 95% CI: 1.2–5.0, p=0.02). For success in antiangiogenic therapy, better understanding about tumor vasculature biology is needed.

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

2018 ◽  
Vol 18 (6) ◽  
pp. 832-836
Author(s):  
Giuseppe Buono ◽  
Francesco Schettini ◽  
Francesco Perri ◽  
Grazia Arpino ◽  
Roberto Bianco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Translational Research ◽  
Cell Biology ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Heterogeneity ◽  
Therapeutic Implications ◽  
The Impact

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors “omics”, including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research. </P><P> It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

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