Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma

Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.

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Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells

Frontiers in Immunology ◽

10.3389/fimmu.2020.626812 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Liang ◽

Napoleone Ferrara

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Iron Metabolism ◽

Immune Cells ◽

Stromal Cells ◽

Epidemiological Studies ◽

Innate Immune ◽

Innate Immune Cells ◽

Cancer Initiation ◽

Iron Binding Proteins

Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.

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The Role of Innate Immune Cells in Tumor Invasion and Metastasis

Cancers ◽

10.3390/cancers13235885 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5885

Author(s):

Yu-Kuan Huang ◽

Rita A. Busuttil ◽

Alex Boussioutas

Keyword(s):

Tumor Cells ◽

Cancer Progression ◽

Immune Cells ◽

Tumor Invasion ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cells ◽

Invasion And Metastasis ◽

Immune Therapies

Metastasis is considered one of the hallmarks of cancer and enhanced tumor invasion and metastasis is significantly associated with cancer mortality. Metastasis occurs via a series of integrated processes involving tumor cells and the tumor microenvironment. The innate immune components of the microenvironment have been shown to engage with tumor cells and not only regulate their proliferation and survival, but also modulate the surrounding environment to enable cancer progression. In the era of immune therapies, it is critical to understand how different innate immune cell populations are involved in this process. This review summarizes recent literature describing the roles of innate immune cells during the tumor metastatic cascade.

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P.047 IDH mutations are associated with pro-inflammatory microglia and macrophages in heterogeneously infiltrated glioblastomas

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.149 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S28-S28

Author(s):

CC Poon ◽

R Yang ◽

T Sheikh ◽

K Liu ◽

S Sarkar ◽

...

Keyword(s):

Immune Cells ◽

Cell Sorting ◽

Inflammatory Infiltrate ◽

Innate Immune ◽

Innate Immune Cells ◽

Cell Surface Markers ◽

Tumor Surveillance ◽

Idh Mutations ◽

Inflammatory Phenotype ◽

Immunologic Status

Background: CNS innate immune cells, microglia and macrophages (MMs), are the largest component of the inflammatory infiltrate in glioblastoma (GBM). They initially participate in tumor surveillance, but are co-opted by GBM to further angiogenesis and invasion. There are no effective immunotherapies against GBM in part because GBM-associated MMs are not well understood. We hypothesized that the extent and inflammatory phenotype of MM infiltration into GBM is variable between patients. This variability could have important implications on immunotherapy selection and treatment outcomes. Methods: Using automated quantitation of fluorescently labeled human GBMs, flow cytometry/live cell sorting, collection of conditioned GBM-associated MM media, and corroboration with TCGA and previously published scRNA-seq data, we have uncovered there is surprisingly marked variation in the amount of MM infiltration between tumors. Results: MM infiltration can range from almost non-existent, to comprising ~70% of GBM cells. By detecting cell surface markers and secreted cytokines, we determined that a mixture of pro- and anti-inflammatory MMs are found in each tumor. The overall inflammatory phenotype did not depend on the amount of infiltration. Interestingly, IDH-mutant GBM-associated MMs are more pro-inflammatory and less heterogeneous than IDH-wildtype GBMs. Conclusions: Taken together, the highly variable immunologic status of GBMs suggests the success of immunotherapies hinges on selecting appropriately vulnerable tumors.

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