• IMMUNE NETWORK
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• v.20 no.1
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• pp.4.1-4.17
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• 2020

Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.

• Oncology Letters
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• v.18 no.5
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• pp.4645-4650
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• 2019

Tumor microenvironment serves an important role in tumor growth and metastasis. Cancer cells can promote growth and malignancy by altering the surrounding stroma. Cancer-associated fibroblast (CAF) are an abundant cell type present within the tumor microenvironment and provide tumorigenic features by secreting cytokines. In the current study, the CAF-mediated invasion of oral squamous cell carcinoma (OSCC) was investigated and the associated mechanisms were elucidated. Cancer invasion was estimated using a Matrigel-coated Transwell chamber and FITC-gelatin matrix. To verify the effect of the tumor microenvironment, conditioned media (CM) from normal fibroblast (NF) and CAFs were prepared. An ELISA was performed to estimate the level of IL-1β. A proteome profiler human protease array was performed to verify the proteases affected by stimulation with CM, from CAF. Recombinant IL-1β protein increased the invasion of OSCC cells. IL-1β expression was higher in CAF than NF. CM from CAF (CM-CAF) increased cancer invasion and FITC-gelatin matrix degradation. The invasive capacity provided by CAF was abrogated by an IL-1 receptor (IL-1R) antagonist. Additionally, CM-CAF increased the secretion of ADAM 9 and Kallikrein 11 from OSCC cells. The invasion activity by CM-CAF was partially abrogated by the neutralization of ADAM 9 or Kallikrein 11. In conclusion, by providing stromal factor, CAFs were a critical inducer of OSCC invasion, and CAF secretes the required amount of IL-1β to increase cancer invasion activity. The invasive capacity of CAF was identified to be IL-1R-dependent. ADAM 9 and Kallikrein 11 were influencing factors involved in the increase of CAF-mediated cancer invasion.

• Development and Reproduction
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• v.27 no.4
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• pp.167-174
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• 2023

Development of hepatocellular carcinoma (HCC) is driven by a multistep and long-term process. Because current therapeutic strategies are limited for HCC patients, there are increasing demands for understanding of immunotherapy, which has made technological and conceptual innovations in the treatment of cancer. Here, I discuss HCC immunotherapy in the view of interaction between liver resident cells and immune cells.

• Molecules and Cells
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• v.46 no.2
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• pp.99-105
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• 2023

Tumors are surrounded by a variety of tumor microenvironmental cells. Profiling individual cells within the tumor tissues is crucial to characterize the tumor microenvironment and its therapeutic implications. Since single-cell technologies are still not cost-effective, scientists have developed many statistical deconvolution methods to delineate cellular characteristics from bulk transcriptome data. Here, we present an overview of 20 deconvolution techniques, including cutting-edge techniques recently established. We categorized deconvolution techniques by three primary criteria: characteristics of methodology, use of prior knowledge of cell types and outcome of the methods. We highlighted the advantage of the recent deconvolution tools that are based on probabilistic models. Moreover, we illustrated two scenarios of the common application of deconvolution methods to study tumor microenvironments. This comprehensive review will serve as a guideline for the researchers to select the appropriate method for their application of deconvolution.

• Molecules and Cells
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• v.43 no.6
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• pp.539-550
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• 2020

Glioblastoma multiforme (GBM) is a fatal malignant tumor that is characterized by diffusive growth of tumor cells into the surrounding brain parenchyma. However, the diffusive nature of GBM and its relationship with the tumor microenvironment (TME) is still unknown. Here, we investigated the interactions of GBM with the surrounding microenvironment in orthotopic xenograft animal models using two human glioma cell lines, U87 and LN229. The GBM cells in our model showed different features on the aspects of cell growth rate during their development, dispersive nature of glioma tumor cells along blood vessels, and invasion into the brain parenchyma. Our results indicated that these differences in the two models are in part due to differences in the expression of CXCR4 and STAT3, both of which play an important role in tumor progression. In addition, the GBM shows considerable accumulation of resident microglia and peripheral macrophages, but polarizes differently into tumor-supporting cells. These results suggest that the intrinsic factors of GBM and their interaction with the TME determine the diffusive nature and probably the responsiveness to non-cancer cells in the TME.

• Journal of Ginseng Research
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• v.43 no.3
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• pp.421-430
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• 2019

Background: The ginsenoside Rg3, one of active components of red ginseng, has chemopreventive and anticancer potential. Cancer stem cells retain self-renewal properties which account for cancer recurrence and resistance to anticancer therapy. In our present study, we investigated whether the standardized Korean Red Ginseng extract (RGE) and Rg3 could modulate the manifestation of breast cancer stem cell-like features through regulation of self-renewal activity. Methods: The effects of RGE and Rg3 on the proportion of $CD44^{high}/CD24^{low}$ cells, as representative characteristics of stem-like breast cancer cells, were determined by flow cytometry. The mammosphere formation assay was performed to assess self-renewal capacities of breast cancer cells. Aldehyde dehydrogenase activity of MCF-7 mammospheres was measured by the ALDEFLUOR assay. The expression levels of Sox-2, Bmi-1, and P-Akt and the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres were verified by immunoblot analysis. Results: Both RGE and Rg3 decreased the viability of breast cancer cells and significantly reduced the populations of $CD44^{high}/CD24^{low}$ in MDA-MB-231 cells. RGE and Rg3 treatment attenuated the expression of Sox-2 and Bmi-1 by inhibiting the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres. Suppression of the manifestation of breast cancer stem cell-like properties by Rg3 was mediated through the blockade of Akt-mediated self-renewal signaling. Conclusion: This study suggests that Rg3 has a therapeutic potential targeting breast cancer stem cells.

• Journal of Gastric Cancer
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• v.17 no.4
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• pp.384-393
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• 2017

Purpose: The tumor microenvironment is known to be associated with the metabolic activity of cancer cells and local immune reactions. We hypothesized that glucose metabolism measured by 2-deoxy-2-($^{18}F$)fluoro-D-glucose ($^{18}F-FDG$) positron emission tomography (PET)-computed tomography (CT) ($^{18}F-FDG$ PET-CT) would be associated with local immune responses evaluated according to the presence of tumor infiltrating lymphocytes (TILs). Materials and Methods: We retrospectively reviewed 56 patients who underwent $^{18}F-FDG$ PET-CT prior to gastrectomy. In resected tumor specimens, TIL subsets, including cluster of differentiation (CD) 3, CD4, CD8, Forkhead box P3 (Foxp3), and granzyme B, were subjected to immunohistochemical analysis. The prognostic nutritional index (PNI) was calculated as: ($10{\times}serum$ albumin value)+($0.005{\times}peripheral$ lymphocyte counts). Additionally, the maximum standard uptake value ($SUV_{max}$) was calculated to evaluate the metabolic activity of cancer cells. Results: The $SUV_{max}$ was positively correlated with larger tumor size (R=0.293; P=0.029) and negatively correlated with PNI (R=-0.407; P=0.002). A higher $SUV_{max}$ showed a marginal association with higher CD3 (+) T lymphocyte counts (R=0.227; P=0.092) and a significant association with higher Foxp3 (+) T lymphocyte counts (R=0.431; P=0.009). No other clinicopathological characteristics were associated with $SUV_{max}$ or TILs. Survival analysis, however, indicated that neither $SUV_{max}$ nor Foxp3 held prognostic significance. Conclusions: FDG uptake on PET-CT could be associated with TILs, especially regulatory T cells, in gastric cancer. This finding may suggest that PET-CT could be of use as a non-invasive tool for monitoring the tumor microenvironment in patients with gastric cancer.

• Molecules and Cells
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• v.39 no.12
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• pp.847-854
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• 2016

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slowergrowing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy.

• BMB Reports
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• v.56 no.1
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• pp.24-31
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• 2023

Urological cancers such as kidney, bladder, prostate, and testicular cancers are the most common types of cancers worldwide with high mortality and morbidity. To date, traditional cell lines and animal models have been broadly used to study pre-clinical applications and underlying molecular mechanisms of urological cancers. However, they cannot reflect biological phenotypes of real tissues and clinical diversities of urological cancers in vitro system. In vitro models cannot be utilized to reflect the tumor microenvironment or heterogeneity. Cancer organoids in three-dimensional culture have emerged as a promising platform for simulating tumor microenvironment and revealing heterogeneity. In this review, we summarize recent advances in prostate and kidney cancer organoids regarding culture conditions, advantages, and applications of these cancer organoids.

• BMB Reports
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• v.48 no.5
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• pp.295-300
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• 2015

Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor $ADR{\beta}2$ involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors. [BMB Reports 2015; 48(5): 295-300]