Functional Regulation of Ginsenosides on Myeloid Immunosuppressive Cells in the Tumor Microenvironment

Ginsenosides, the key components isolated from ginseng, have been extensively studied in antitumor treatment. Numerous studies have shown that ginsenosides have direct function in tumor cells through the induction of cancer cell apoptosis and the inhibition of cancer cell growth and enhance the antitumor immunity through the activation of cytotoxic T lymphocytes and natural killer cells. However, little is known about the function of ginsenosides on myeloid immunosuppressive cells including dendritic cells in tumor, tumor-associated macrophages, and myeloid-derived suppressor cells in the tumor microenvironments. Those myeloid immunosuppressive cells play important roles in promoting tumor angiogenesis, invasion, and metastasis. In the review, we summarize the regulatory functions of ginsenosides on myeloid immunosuppressive cells in tumor microenvironment, providing the novel therapeutic methods for clinical cancer treatment.

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Pro-Tumor and Anti-Tumor Functions of IL-17 and of TH17 Cells in Tumor Microenvironment

Acta Medica Bulgarica ◽

10.1515/amb-2016-0019 ◽

2016 ◽

Vol 43 (2) ◽

pp. 68-79 ◽

Cited By ~ 1

Author(s):

M. Gulubova ◽

J. Ananiev ◽

M. Ignatova ◽

K. Halacheva

Keyword(s):

T Cells ◽

Cell Differentiation ◽

Tumor Microenvironment ◽

Th17 Cells ◽

T Helper ◽

Main Attention ◽

Tumor Microenvironments ◽

Th17 Cell Differentiation ◽

Regulatory Functions

Summary The current review reveals the seven subclasses of CD4+ T helper cells, i.e. Th1, Th2, Th9, Th17, Th22, regulatory T cells and Tfh, the cytokines produced by them and their role in tumor microenvironment. Main attention was paid to IL-17 and Th17 cells. IL-17-producing cells were described, among which were Treg17 cells and Tc17 cells. The transcription factors, engaged in the activation of Th17 cell differentiation were reviewed. It was shown that Th17 cells might possess regulatory functions in tumor microenvironments that directs toward immunosuppression. The reciprocity between Treg and Th17 cells is realized when the production of a large amount of TGF-β in tumors causes Treg cell differentiation, and the addition of IL-6 shifts the differentiation of naïve T cells to Th17 cells. The main pro-tumor role of IL-17 is the promotion of tumor angiogenesis through stimulation of fibroblasts and endothelial cells. The antitumor functions of IL-17 are associated with enhancement of cytotoxic activity of tumor specific CTL cells and with angiogenesis that provide channels through which immune cells might invade tumor and promote antitumor immunity.

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Potential alteration of tumor microenvironments by β-mercaptoethanol

Future Oncology ◽

10.2217/fon-2020-0801 ◽

2020 ◽

Author(s):

Robert E Click

Keyword(s):

Molecular Weight ◽

Tumor Microenvironment ◽

Immune Checkpoint ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Survival Rates ◽

Suppressor Cells ◽

Low Molecular Weight ◽

Uptake Inhibition ◽

Tumor Microenvironments

The therapeutic effectiveness of immune checkpoint inhibitors in cancer patients is quite profound. However, it is generally accepted that further progress is curtailed by accompanying adverse events and by low cure rates linked to the tumor microenvironment. The multitudes of immune processes altered by low-molecular-weight thiols published over the past decades suggest they have potential to alter tumor microenvironment processes which could result in an increase in immune checkpoint inhibitor survival rates. Based on one of the most studied and most potent low-molecular-weight thiols, β-mercaptoethanol (BME), it is proposed that clinical assessment be undertaken to identify any BME benefits with relevance for proliferation/differentiation of immune cells, lymphocyte exhaustion, immunogenicity of tumor antigens and inactivation of suppressor cells/factors. The BME alterations projected to be most effective are: maintenance/replacement of glutathione in lymphocytes via facilitation of cysteine uptake, inhibition of suppressor cells/soluble factors and inactivation of free-radical, reactive oxygen species.

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Modulation of Cancer Cell Growth and Progression by Caveolin-1 in the Tumor Microenvironment

Advances in Experimental Medicine and Biology - Tumor Microenvironment ◽

10.1007/978-3-030-50224-9_4 ◽

2020 ◽

pp. 63-74

Author(s):

Hyo-Jin Yoon ◽

Young-Joon Surh

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Cancer Cell Growth ◽

Caveolin 1

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Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment

Oncotarget ◽

10.18632/oncotarget.13609 ◽

2016 ◽

Vol 8 (1) ◽

pp. 1290-1303 ◽

Cited By ~ 17

Author(s):

Zongze Shen ◽

Xing Qin ◽

Ming Yan ◽

Rongrong Li ◽

Gang Chen ◽

...

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Cancer Associated Fibroblasts ◽

Cancer Cell Growth

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Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth

Cell Metabolism ◽

10.1016/j.cmet.2016.10.011 ◽

2016 ◽

Vol 24 (5) ◽

pp. 685-700 ◽

Cited By ~ 131

Author(s):

Lifeng Yang ◽

Abhinav Achreja ◽

Tsz-Lun Yeung ◽

Lingegowda S. Mangala ◽

Dahai Jiang ◽

...

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Glutamine Synthetase ◽

Cancer Cell ◽

Cancer Cell Growth

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Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment

Cancers ◽

10.3390/cancers12071960 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1960

Author(s):

Tsubasa Miyazaki ◽

Eiichi Ishikawa ◽

Narushi Sugii ◽

Masahide Matsuda

Keyword(s):

Tumor Microenvironment ◽

Immune Checkpoint ◽

Malignant Tumors ◽

Suppressor Cells ◽

Treatment Resistance ◽

Glioma Initiating Cells ◽

Programmed Cell Death 1 ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Tumor Microenvironment ◽

Immunosuppressive Cells

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

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Subverting Subversion: A Review on the Breast Cancer Microenvironment and Therapeutic Opportunities

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s29423 ◽

2015 ◽

Vol 9s2 ◽

pp. BCBCR.S29423 ◽

Cited By ~ 4

Author(s):

Ethan Rothschild ◽

Debabrata Banerjee

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Adaptive Immune Response ◽

Suppressor Cells ◽

Cancer Cell Growth ◽

Chemotherapy Drugs ◽

Tumor Growth And Metastasis ◽

Novel Target

This review combines the recent research on the subject of tumor immunology and methods of correcting the immune system's reaction to the tumor microenvironment while impeding the survival and growth of tumor cells, with a focus on breast cancer. Induction of hypoxia-inducible genes in the microenvironment leads to lowering of its pH. This impedes the adaptive immune response and acts to recruit cells of the immune system, which suppress the immune response. Regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and their derivatives coordinate an anti-autoimmunity response and a healing response in concert with tumor-secreted cytokines, enzymes, and antigens. Together, they suppress a proper immune reaction to tumor cells and promote cellular reproduction ( Fig. 1 ). In addition, the hypoxia-inducible response and components of the tumor microenvironment such as cancer-associated fibroblasts (CAFs) also create an ideal environment for tumor growth and metastasis via neoangiogenesis and increased motility. Broad-spectrum chemotherapy drugs are problematic as breast cancer cells develop resistance through selective loss of a novel target and downregulation of apoptotic factors. A better understanding of the tumor microenvironment offers new therapeutic opportunities to rescue the immune response, inhibit cancer cell growth pathways, and subvert the tumor microenvironment with little toxicity and side effects.

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Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Biology ◽

10.3390/biology9110380 ◽

2020 ◽

Vol 9 (11) ◽

pp. 380

Author(s):

Kyra E. de de Goede ◽

Amber J. M. Driessen ◽

Jan Van den Bossche

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cell ◽

Immune Cells ◽

Cell Metabolism ◽

Cancer Therapies ◽

Macrophage Phenotype ◽

Cancer Cell Growth ◽

Metabolic Conditions ◽

And Function

Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

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The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer

npj Breast Cancer ◽

10.1038/s41523-021-00259-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhenbo Tu ◽

Johannes Schmoellerl ◽

Odette Mariani ◽

Yurong Zheng ◽

Yi Hu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Prognostic Indicator ◽

Adverse Outcomes ◽

Cytokine Signaling ◽

Cancer Cell Growth

AbstractThe development of triple-negative breast cancer (TNBC) is critically regulated by certain tumor-microenvironment-associated cells called mesenchymal stem/stromal cells (MSCs), which we and others have shown promote TNBC progression by activating pro-malignant signaling in neighboring cancer cells. Characterization of these cascades would better our understanding of TNBC biology and bring about therapeutics that eliminate the morbidity and mortality associated with advanced disease. Here, we focused on the emerging class of RNAs called long non-coding RNAs or lncRNAs and utilized a MSC-supported TNBC progression model to identify specific family members of functional relevance to TNBC pathogenesis. Indeed, although some have been described to play functional roles in TNBC, activities of lncRNAs as mediators of tumor-microenvironment-driven TNBC development remain to be fully explored. We report that MSCs stimulate robust expression of LINC01119 in TNBC cells, which in turn induces suppressor of cytokine signaling 5 (SOCS5), leading to accelerated cancer cell growth and tumorigenesis. We show that LINC01119 and SOCS5 exhibit tight correlation across multiple breast cancer gene sets and that they are highly enriched in TNBC patient cohorts. Importantly, we present evidence that the LINC01119-SOCS5 axis represents a powerful prognostic indicator of adverse outcomes in TNBC patients, and demonstrate that its repression severely impairs cancer cell growth. Altogether, our findings identify LINC01119 as a major driver of TNBC development and delineate critical non-coding RNA theranostics of potential translational utility in the management of advanced TNBC, a class of tumors in most need of effective and targeted therapy.

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