scholarly journals The Interplay between Glioblastoma and Its Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2257
Author(s):  
Mark Dapash ◽  
David Hou ◽  
Brandyn Castro ◽  
Catalina Lee-Chang ◽  
Maciej S. Lesniak
Keyword(s):  
Tumor Microenvironment ◽  
Patient Outcomes ◽  
Poor Prognosis ◽  
Primary Brain Tumor ◽  
Major Contributor ◽  
Complex Interplay ◽  
Environmental Pressures ◽  
The Poor ◽  
Adaptive Nature ◽  
Poor Efficacy

GBM is the most common primary brain tumor in adults, and the aggressive nature of this tumor contributes to its extremely poor prognosis. Over the years, the heterogeneous and adaptive nature of GBM has been highlighted as a major contributor to the poor efficacy of many treatments including various immunotherapies. The major challenge lies in understanding and manipulating the complex interplay among the different components within the tumor microenvironment (TME). This interplay varies not only by the type of cells interacting but also by their spatial distribution with the TME. This review highlights the various immune and non-immune components of the tumor microenvironment and their consequences f the efficacy of immunotherapies. Understanding the independent and interdependent aspects of the various sub-populations encapsulated by the immune and non-immune components will allow for more targeted therapies. Meanwhile, understanding how the TME creates and responds to different environmental pressures such as hypoxia may allow for other multimodal approaches in the treatment of GBM. Ultimately, a better understanding of the GBM TME will aid in the development and advancement of more effective treatments and in improving patient outcomes.

scholarly journals BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1262 ◽  
Author(s):  
Karisa C. Schreck ◽  
Stuart A. Grossman ◽  
Christine A. Pratilas
Keyword(s):  
Brain Tumors ◽  
Poor Prognosis ◽  
Primary Brain Tumor ◽  
High Grade ◽  
Braf Mutations ◽  
Mek Inhibitors ◽  
Primary Brain Tumors ◽  
The Poor ◽  
Oncogenic Mutations ◽  
Tumor Types

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.

scholarly journals CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

2021 ◽  
Vol 11 ◽  
Author(s):  
Gurcan Gunaydin
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Poor Prognosis ◽  
Cancer Associated Fibroblasts ◽  
Mutual Relationship ◽  
Complex Interplay ◽  
Tumor Immune Evasion ◽  
Mechanisms Of Carcinogenesis

Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

scholarly journals Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and their Implications for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4255
Author(s):  
Rikke Sick Andersen ◽  
Atul Anand ◽  
Dylan Scott Lykke Harwood ◽  
Bjarne Winther Kristensen
Keyword(s):  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Therapeutic Strategies ◽  
The Poor ◽  
Temozolomide Chemotherapy

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

scholarly journals What Mediates Fibrosis in the Tumor Microenvironment of Clear Renal Cell Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenbo Yang ◽  
Caipeng Qin ◽  
Jingli Han ◽  
Songchen Han ◽  
Wenjun Bai ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Cell Counting ◽  
Immunohistochemical Method ◽  
Biological Behavior ◽  
Type I ◽  
The Poor ◽  
Low Expression

Previous studies have demonstrated that direct targeting of interstitial cancer-associated fibroblasts (CAF) and tumor fibrosis alone seemed to be an unpromising treatment option for malignant tumors. Therefore, it is necessary to further explore the mechanism of the influence of collagen and tumor fibrosis on the biological behavior of malignant tumors. The current study aimed to explore the effect of intratumor fibrosis on the prognosis of renal clear cell carcinoma (ccRCC) and its mechanism. With the bioinformatic analysis of The Cancer Genome Atlas (TCGA) database (n = 537), the study showed that high Collagen type I α 1 (COL1A1) mRNA expression indicated the poor prognosis of ccRCC patients compared with low expression ones. We further used the Two-photon-excited fluorescence (TPEF)/second harmonic generation (SHG) microscopy to determine the intratumor fibrosis of 68 patients with surgical resection of ccRCC and confirmed that a high fibrosis level in the tumor was associated with a poor prognosis compared with patients with low expression (Progression-Free Survival: p = 0.030). We further measured the protein chips of 640 cytokines in ccRCC specimens and found that several cytokines, including prolactin (PRL), were associated with the degree of fibrosis in the tumor, as confirmed by the prolactin receptor (PRLR) immunohistochemical method. In addition, the study showed that PRLR expression decreased significantly in the ccRCC compared with adjacent normal tissue (p < 0.05). Our research shows that low expression of PRLR predicted the poor survival of the patient. We used the Cell Counting Kit-8 experiment, the transwell and the plate clone formation assay to evaluate the role of PRL in the 7860 and the ACHN cell lines. We found that PRL promoted ccRCC cell proliferation and migration. JAK-STAT3 activation was found in the high prolactin expression group by mass spectrum analysis. This study delineated the fibrosis-based tumor microenvironment characteristics of ccRCC. PRL/PRLR may be involved in the fibrosis process and are essential prognostic risk factors for ccRCC.

scholarly journals Identification of a Prognostic Model Based on 2-Gene Signature and Analysis of Corresponding Tumor Microenvironment in Alcohol-Related Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yong Guo ◽  
Jiejun Hu ◽  
Zhibo Zhao ◽  
Guochao Zhong ◽  
Jianping Gong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Poor Prognosis ◽  
Prognostic Model ◽  
Cox Regression ◽  
Malignant Tumors ◽  
High Risk Group ◽  
Hub Genes ◽  
Clinical Value ◽  
The Poor

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with the poor prognosis. Nowadays, alcohol is becoming a leading risk factor of HCC in many countries. In our study, we obtained the DEGs in alcohol-related HCC through two databases (TCGA and GEO). Subsequently, we performed enrichment analyses (GO and KEGG), constructed the PPI network and screened the 53 hub genes by Cytoscape. Two genes (BUB1B and CENPF) from hub genes was screened by LASSO and Cox regression analyses to construct the prognostic model. Then, we found that the high risk group had the worse prognosis and verified the clinical value of the risk score in alcohol-related HCC. Finally, we analyzed the tumor microenvironment between high and low risk groups through CIBERSORT and ESTIMATE. In summary, we constructed the two-gene prognostic model that could predict the poor prognosis in patients with alcohol-related HCC.

scholarly journals Methylxanthines: Potential Therapeutic Agents for Glioblastoma

2019 ◽  
Vol 12 (3) ◽  
pp. 130
Author(s):  
Daniel Pérez-Pérez ◽  
Iannel Reyes-Vidal ◽  
Elda Georgina Chávez-Cortez ◽  
Julio Sotelo ◽  
Roxana Magaña-Maldonado
Keyword(s):  
Cancer Progression ◽  
Poor Prognosis ◽  
Median Overall Survival ◽  
Primary Brain Tumor ◽  
Therapeutic Agents ◽  
The Poor ◽  
Pde Inhibitors ◽  
Anti Cancer ◽  
Cell Processes ◽  
Cancer Agent

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM.

scholarly journals Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1850
Author(s):  
Justine Cinier ◽  
Margaux Hubert ◽  
Laurie Besson ◽  
Anthony Di Roio ◽  
Céline Rodriguez ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Poor Prognosis ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Major Function ◽  
Normal Tissues ◽  
Tumor Environment ◽  
Plastic Transformation

Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

scholarly journals The Effect of Heterogenous Subregions in Glioblastomas on Survival Stratification: A Radiomics Analysis Using the Multimodality MRI

2021 ◽  
Vol 20 ◽  
pp. 153303382110330
Author(s):  
Lulu Yin ◽  
Yan Liu ◽  
Xi Zhang ◽  
Hongbing Lu ◽  
Yang Liu
Keyword(s):  
Poor Prognosis ◽  
Intratumor Heterogeneity ◽  
Short Term ◽  
Prognostic Information ◽  
Manual Delineation ◽  
Flair Sequence ◽  
The Poor ◽  
Contrast Enhanced ◽  
Mri Sequences

Intratumor heterogeneity is partly responsible for the poor prognosis of glioblastoma (GBM) patients. In this study, we aimed to assess the effect of different heterogeneous subregions of GBM on overall survival (OS) stratification. A total of 105 GBM patients were retrospectively enrolled and divided into long-term and short-term OS groups. Four MRI sequences, including contrast-enhanced T1-weighted imaging (T1C), T1, T2, and FLAIR, were collected for each patient. Then, 4 heterogeneous subregions, i.e. the region of entire abnormality (rEA), the regions of contrast-enhanced tumor (rCET), necrosis (rNec) and edema/non-contrast-enhanced tumor (rE/nCET), were manually drawn from the 4 MRI sequences. For each subregion, 50 radiomics features were extracted. The stratification performance of 4 heterogeneous subregions, as well as the performances of 4 MRI sequences, was evaluated both alone and in combination. Our results showed that rEA was superior in stratifying long-and short-term OS. For the 4 MRI sequences used in this study, the FLAIR sequence demonstrated the best performance of survival stratification based on the manual delineation of heterogeneous subregions. Our results suggest that heterogeneous subregions of GBMs contain different prognostic information, which should be considered when investigating survival stratification in patients with GBM.

scholarly journals Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001341
Author(s):  
Chunxiao Li ◽  
Xiaofei Xu ◽  
Shuhua Wei ◽  
Ping Jiang ◽  
Lixiang Xue ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumor Immunotherapy ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Future Prospects ◽  
Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

scholarly journals Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival

2021 ◽  
Author(s):  
Juan Tong ◽  
Lei Zhang ◽  
Huilan Liu ◽  
Xiucai Xu ◽  
Changcheng Zheng ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Chemotherapy Group ◽  
Blood Transplantation ◽  
The Poor ◽  
First Complete Remission

AbstractThis is a retrospective study comparing the effectiveness of umbilical cord blood transplantation (UCBT) and chemotherapy for patients in the first complete remission period for acute myeloid leukemia with KMT2A-MLLT3 rearrangements. A total of 22 patients were included, all of whom achieved first complete remission (CR1) through 1–2 rounds of induction chemotherapy, excluding patients with an early relapse. Twelve patients were treated with UCBT, and 10 patients were treated with chemotherapy after 2 to 4 courses of consolidation therapy. The 3-year overall survival (OS) of the UCBT group was 71.3% (95% CI, 34.4–89.8%), and that of the chemotherapy group was 10% (95% CI, 5.89–37.3%). The OS of the UCBT group was significantly higher than that of the chemotherapy group (P = 0.003). The disease-free survival (DFS) of the UCBT group was 60.8% (95% CI, 25.0–83.6%), which was significantly higher than the 10% (95% CI, 5.72–35.8%) of the chemotherapy group (P = 0.003). The relapse rate of the UCBT group was 23.6% (95% CI, 0–46.8%), and that of the chemotherapy group was 85.4% (95% CI, 35.8–98.4%), which was significantly higher than that of the UCBT group (P < 0.001). The non-relapse mortality (NRM) rate in the UCBT group was 19.8% (95% CI, 0–41.3%), and that in the chemotherapy group was 0.0%. The NRM rate in the UCBT group was higher than that in the chemotherapy group, but there was no significant difference between the two groups (P = 0.272). Two patients in the UCBT group relapsed, two died of acute and chronic GVHD, and one patient developed chronic GVHD 140 days after UCBT and is still alive, so the GVHD-free/relapse-free survival (GRFS) was 50% (95% CI, 17.2–76.1%). AML patients with KMT2A-MLLT3 rearrangements who receive chemotherapy as their consolidation therapy after CR1 have a very poor prognosis. UCBT can overcome the poor prognosis and significantly improve survival, and the GRFS for these patients is very good. We suggest that UCBT is a better choice than chemotherapy for KMT2A-MLLT3 patients.

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