scholarly journals Multiple Faces of the Glioblastoma Microenvironment

2022 ◽  
Vol 23 (2) ◽  
pp. 595
Author(s):  
Alina Simona Șovrea ◽  
Bianca Boșca ◽  
Carmen Stanca Melincovici ◽  
Anne-Marie Constantin ◽  
Andreea Crintea ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Leading Edge ◽  
Modern Trend ◽  
Peritumoral Tissue

The tumor microenvironment is a highly dynamic accumulation of resident and infiltrating tumor cells, responsible for growth and invasion. The authors focused on the leading-edge concepts regarding the glioblastoma microenvironment. Due to the fact that the modern trend in the research and treatment of glioblastoma is represented by multiple approaches that target not only the primary tumor but also the neighboring tissue, the study of the microenvironment in the peritumoral tissue is an appealing direction for current and future therapies.

Platelet Depletion Reduces Tumor Hypoxia and Metastasis Mediated by Met Signaling Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3321-3321
Author(s):  
Rong Li ◽  
Meiping Ren ◽  
Ni Chen ◽  
Mao Luo ◽  
Jianbo Wu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Hypoxia ◽  
Hemoglobin Content ◽  
Melanoma Cancer ◽  
And Control ◽  
Platelet Depletion

Abstract Abstract 3321 Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hemorrhagic metastasis. However, the role of platelets in the tumor growth, angiogenesis, and metastasis initiation remains undefined. The B16/F10 melanoma cancer cells model of metastasis and the Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model were used for this purpose. Using induction of thrombocytopenia, primary tumor growth was monitored and every 3 days anti-GPIbα or rat IgG injections were initiated when tumor reached ∼500mm3and continued until tumor reached to 3 weeks. We showed that platelet depletion had no change in tumor growth but reduced metastasis. Platelet depletion significantly increased pericyte coverage and reduced vascular density compared with control mice. We evaluated the ratio of fluorescence intensities within the plasma and tumor following injection of mice with FITC-dextran. We found that the FITC-dextran was similarly deposited into the tumor tissue in either platelet-depleted or control mice, indicating that tumor vessel perfusion did not differ in either platelet-depleted or control mice. To further gain insight into the molecular mechanisms associated with reduced metastasis resulting from platelet depletion, we assessed hypoxia levels by examining pimonidazole adduct formation in the tumors of platelet-depleted and control mice and found decreased hypoxic levels in the platelet-depleted tumors. In addition, expression of the hypoxia-inducible transcription factor HIF-1α was also significantly reduced in the tumors of platelet-depleted mice. Tumor hypoxia is strongly associated with deposition of hemoglobin. We measured the intratumor hemoglobin content, reflecting the level of erythrocytes extravasation. The hemoglobin content in the tumors of mice with platelet-depletion was significantly higher than that of control mice (172.11 ± 20.2 g/L/g Vs. 110.28 ± 12.4 g/L/g, p<0.05) Based on the known induction effects of hypoxia and cancer invasiveness on the expression and activation of the proinvasive tyrosine kinase receptor Met, we analyzed total protein and tyrosine phosphorylation levels of Met in both platelet-depleted and control mice. Western blotting analysis revealed that platelet-depletion caused a significantly decrease of both total Met and phosph-Met in tumors when compared to tumors from control mice. To evaluate intratumoral growth factor level, microdialysis was performed after 3 weeks and there was a significant decrease of extracellular VEGF and TNF-β in platelet depletion mice compared with control mice. Recent studies demonstrated that abundant platelets were detected in the tumor microenvironment apart from the vasculature. Based on the finding platelets in contact with tumor cells outside the bloodstream, we examined the functional effects of co-implantation of B16/F10 tumor cells with platelets on tumor progression and metastasis. B16/F10 melanoma cancer cells were implanted into back of wild type mice. During a 3-weeks growth, co-implantation of B16/F10 with platelets not only led to promoted tumor volume (3968 ± 296 mm3Vs. 2956 ± 180 mm3, p<0.05) and weight (5.529 ± 0.35 g Vs. 3.943 ± 0.738 g, p<0.05 ) compared with B16/F10 alone implantation, but also led to an increase in metastasis. Furthermore, in vitro co-culture of B16/F10 cancer cells with platelets showed a significant increase in B16/F10 cancer cells invasion compared with B16/F10 cancer cells alone. In conclusion, our findings demonstrate for the first time that platelets play a critical role in the initiation of tumor metastasis. Moreover, our findings suggest that platelets within the primary tumor microenvironment are likely involved in tumor progression and metastasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

2020 ◽  
Author(s):  
Motomasa Furuse ◽  
Hiroko Kuwabara ◽  
Naokado Ikeda ◽  
Yasuhiko Hattori ◽  
Tomotsugu Ichikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Prognostic Significance ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Biological Factors ◽  
Peritumoral Tissue

Abstract Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7–NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Conclusions: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

scholarly journals PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

2019 ◽  
Author(s):  
Motomasa Furuse ◽  
Hiroko Kuwabara ◽  
Naokado Ikeda ◽  
Yasuhiko Hattori ◽  
Tomotsugu Ichikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Prognostic Significance ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Biological Factors ◽  
Peritumoral Tissue

Abstract Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7–NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Conclusions: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

scholarly journals Tumor Microenvironment: Involved Factors and Signaling Pathways in Epithelial-Mesenchymal Transition

2021 ◽  
Vol 14 (7) ◽  
Author(s):  
Madeh Ghaderi ◽  
Azadeh Niknejad
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Gene Expressions ◽  
Mesenchymal Transition ◽  
Tumor Mass ◽  
Secondary Tumor

Context: Metastasis is a main cause of death in patients with cancer, whereby tumor cells withdraw from the primary site of the tumor mass and produce secondary tumor mass in new sites. Primary tumor cells depart collectively and individually to invade closed and distant sites. Evidence Acquisition: This review considers TME-derived factors that actuate signaling pathways to induce epithelial-mesenchymal transition (EMT). National Center for Biotechnology Information (NCBI) was the main resource. Google Scholar and Scopus were other databases for finding articles. Keywords that were inserted into the search box of databases to identify related articles were ‘metastasis’, ‘invasion’, ‘epithelial-mesenchymal transition’, ‘EMT’, ‘tumor microenvironment’, ‘TME’, ‘TME cells’, and ‘signaling pathway in EMT’. Titles and abstracts of the articles were studied to choose the right articles. Finally, 100 articles were selected to study in detail and use as references. Results: EMT is a type of metastasis that deprives epithelial single-cells of their characteristic features and acquires mesenchymal features facilitating the departure from the primary tumor mass. During EMT, cell-adhesion and apical-basal polarity rapture and cells obtain movement capability. The tumor microenvironment (TME) leads EMT through secretion factors and signaling pathways. As a result of activating these pathways, transcription factors that abolish epithelial gene expressions and augment mesenchymal gene expression are induced. Conclusions: In this review, recent research published in TME and EMT fields were highlighted and critically appraised. Effect of factors-derived TME cells on EMT were manifested that propose favorite targets for a therapeutic goal to inhibit metastasis. However, data about the effect of the combination of TME cells on metastasis have a small part in the literature.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

scholarly journals Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1213
Author(s):  
Zihe Huo ◽  
Mariana Sá Santos ◽  
Astrid Drenckhan ◽  
Stefan Holland-Cunz ◽  
Jakob R. Izbicki ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Tumor Cells ◽  
Cell Lines ◽  
Adhesion Strength ◽  
Primary Tumor ◽  
Carcinoma Cell ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Metastatic Cell ◽  
Carcinoma Cell Lines

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

scholarly journals Primary tumor cells obtained from MNU-induced mammary carcinomas show immune heterogeneity which can be modulated by low-efficiency transfection of CD40L gene

2009 ◽  
Vol 8 (2) ◽  
pp. 136-142 ◽  
Author(s):  
Gunes Esendagli ◽  
Hande Canpinar ◽  
Guldal Yilmaz ◽  
Aysen Gunel-Ozcan ◽  
M. Oguz Guc ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Primary Tumor ◽  
Mammary Carcinomas ◽  
Low Efficiency

scholarly journals Assessment of phagocytic activity in live macrophages-tumor cells co-cultures by Confocal and Nomarski Microscopy

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Dalia Martinez-Marin ◽  
Courtney Jarvis ◽  
Thomas Nelius ◽  
Stéphanie Filleur
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Phagocytic Activity ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Functional Assay ◽  
Loss Of Function ◽  
Multiple Cancer

Abstract Macrophages have been recognized as the main inflammatory component of the tumor microenvironment. Although often considered as beneficial for tumor growth and disease progression, tumor-associated macrophages have also been shown to be detrimental to the tumor depending on the tumor microenvironment. Therefore, understanding the molecular interactions between macrophages and tumor cells in relation to macrophages functional activities such as phagocytosis is critical for a better comprehension of their tumor-modulating action. Still, the characterization of these molecular mechanisms in vivo remains complicated due to the extraordinary complexity of the tumor microenvironment and the broad range of tumor-associated macrophage functions. Thus, there is an increasing demand for in vitro methodologies to study the role of cell–cell interactions in the tumor microenvironment. In the present study, we have developed live co-cultures of macrophages and human prostate tumor cells to assess the phagocytic activity of macrophages using a combination of Confocal and Nomarski Microscopy. Using this model, we have emphasized that this is a sensitive, measurable, and highly reproducible functional assay. We have also highlighted that this assay can be applied to multiple cancer cell types and used as a selection tool for a variety of different types of phagocytosis agonists. Finally, combining with other studies such as gain/loss of function or signaling studies remains possible. A better understanding of the interactions between tumor cells and macrophages may lead to the identification of new therapeutic targets against cancer.

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