• Radiation Oncology Journal
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• v.38 no.1
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• pp.1-10
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• 2020

Radiotherapy (RT) has been used for decades as one of the main treatment modalities for cancer patients. The therapeutic effect of RT has been primarily ascribed to DNA damage leading to tumor cell death. Besides direct tumoricidal effect, RT affects antitumor responses through immune-mediated mechanism, which provides a rationale for combining RT and immunotherapy for cancer treatment. Thus far, for the combined treatment with RT, numerous studies have focused on the immune checkpoint inhibitors and have shown promising results. However, treatment resistance is still common, and one of the main resistance mechanisms is thought to be due to the immunosuppressive tumor microenvironment where myeloid-derived suppressor cells (MDSCs) play a crucial role. MDSCs are immature myeloid cells with a strong immunosuppressive activity. MDSC frequency is correlated with tumor progression, recurrence, negative clinical outcome, and reduced efficacy of immunotherapy. Therefore, increasing efforts to target MDSCs have been made to overcome the resistance in cancer treatments. In this review, we focus on the role of MDSCs in RT and highlight growing evidence for targeting MDSCs in combination with RT to improve cancer treatment.

• Journal of Gastric Cancer
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• v.16 no.1
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• pp.1-7
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• 2016

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra-or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.

• Journal of Korean Dental Science
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• v.15 no.2
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• pp.121-131
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• 2022

Ameloblastoma is the most representative epithelial odontogenic tumor in the craniofacial region. Through several studies on Ameloblastoma that have been conducted so far, we have been able to get closer to the reality of Ameloblastoma. However, groundbreaking insight into the pathophysiology of Ameloblastoma has not yet been provided. This review assessed three aspects of five recently published papers on Ameloblastoma: cancer stem cells, calcium signaling, and tumor microenvironment, and compared them with previous studies on tumor physiology, including cancer. In addition, the characteristics of Ameloblastoma revealed by the experimental methods presented in the currently published five papers provide the possibility of Ameloblastoma as a study model in general tumor or cancer studies. Furthermore, the mechanisms of action of the chemicals identified in the studies support their potential as candidates for the second-line treatment of Ameloblastoma.

• Journal of Applied Biological Chemistry
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• v.65 no.4
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• pp.387-396
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• 2022

Skeletal muscle accounts for about 40-50% of body weight and is an important tissue that performs various functions, such as maintaining posture, supporting soft tissues, maintaining body temperature, and respiration. Cancer, which occurs widely around the world, causes cancer cachexia accompanied by muscular atrophy, which reduces the effectiveness of anticancer drugs and greatly reduces the quality of life and survival rate of cancer patients. Therefore, research to improve cancer cachexia is ongoing. However, there are few studies on the link between cancer and muscle atrophy. Cancer cells exhibit distinct microenvironment and metabolism from tumor cells, including tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), and insulin resistance due to the Warburg effect. Therefore, we summarize the microenvironment and metabolic characteristics of cancer cells, and the molecular mechanisms of muscle atrophy that can be affected by cytokine and insulin resistance. In addition, this suggests the possibility of improving cancer cachexia of substances affecting TAM, TAN, and Warburg effect. We also summarize the mechanisms identified so far through single agents and the signaling pathways mediated by them that may ameliorate cancer cachexia.

• Molecules and Cells
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• v.42 no.7
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• pp.530-545
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• 2019

Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive $CD133^+/CD24^-$ cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.12
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• pp.5273-5280
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• 2016

Objective: To evaluate stromal cells of the bone marrow microenvironment (BMM) in bone marrow trephine biopsy (BMTB) specimens, with a focus on fibronectin, tumor necrosis factor- alpha (TNF-${\alpha}$) and L-selectin in Non-Hodgkin's lymphoma (NHL) patients, before and after therapy. Materials and Methods: A total of 80 de novo NHL patients, 64 with B-cell lymphomas 80%, (follicular cell lymphoma (FCL) in 32, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in 12, and diffuse large cell lymphoma in 20) and 16 with T-cell lymphomas (20%) all diagnosed as T-Lymphoblastic lymphomas, were evaluated before and after therapy. For comparison, 25 age and sex matched BM donors, were included as a control group. BMTB material and BM aspirates were taken for morphological assessment of stromal cells, the plasma of these samples being examined for $TNF{\alpha}$ and L-selectin by ELISA, and fibronectin by radial immunodiffusion (RID). Results: BM stromal cells comprising reticular macrophages and fibroblasts were elevated in 53.3% of NHL cases at diagnosis, while BM fibronectin levels were decreased and BM $TNF{\alpha}$ and L-selectin were higher than in controls (p<0.05). In NHL cases, elevated values of BM $TNF{\alpha}$ and BM L-selectin were associated with signs of aggressive disease, including >1 extra nodal sites, detectable B symptoms, high grade, BM and CNS invasion, and a high International prognostic index (IPI) (p<0.05). Conclusion: BMM components, $TNF{\alpha}$, L-selectin and fibronectin, in NHL can be useful in evaluating disease activity, extent and response to treatment and as prognostic markers according to the IPI.

• BMB Reports
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• v.54 no.2
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• pp.136-141
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• 2021

Thyroid eye disease (TED) is a complex autoimmune disease with a spectrum of signs. we previously reported that trisialoganglioside (GT)1b is significantly overexpressed in the orbital tissue of TED patients, and that exogenous GT1b strongly induced HA synthesis in orbital fibroblasts. However, the signaling pathway in GT1b-induced hyaluronic acid synthase (HAS) expression in orbital fibroblasts from TED patients have rarely been investigated. Here, we demonstrated that GT1b induced phosphorylation of Akt/mTOR in a dose-dependent manner in orbital fibroblasts from TED patients. Both co-treatment with a specific inhibitor for PI3K and siRNA knockdown of TLR2 attenuated GT1b-induced Akt phosphorylation. GT1b significantly induced HAS2 expression at both the transcriptional and translational level, which was suppressed by specific inhibitors of PI3K or Akt/mTOR, and by siRNA knockdown of TLR2. In conclusion, GT1b induced HAS2 in orbital fibroblasts from TED patients via activation of the PI3K-related signaling pathway, dependent on TLR2.

• Biomolecules & Therapeutics
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• v.22 no.5
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• pp.426-430
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• 2014

Prostate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time- and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT- or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6- or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6- and/or DHT-induced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5883-5890
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• 2013

Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related to tumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D in the EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advanced FIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations of SEMA4D expression and M2 macrophage counts in primary tumors and M2 macrophage percentage in ascites (r=0.281 and 0.355, each P<0.05). In the Cox proportional hazard mode, SEMA4D expression was an independent indicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higher expression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants were found than that in a human primary cultured ovarian cell and its supernatant by reversed transcript PCR (RT-PCR), Western blotting and ELISA, respectively. Interestingly, peripheral blood monocytes (MOs) tended towards the M2-polarized macrophage phenotype ($CD163^{high}$) in vitro after human recombined soluble SEMA4D protein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis and could playan important role in promoting tumor dissemination and metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOC warrants further study.

• Molecules and Cells
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• v.43 no.9
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• pp.763-773
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• 2020

Recently, tumor microenvironment (TME) and its stromal constituents have provided profound insights into understanding alterations in tumor behavior. After each identification regarding the unique roles of TME compartments, non-malignant stromal cells are found to provide a sufficient tumorigenic niche for cancer cells. Of these TME constituents, adipocytes represent a dynamic population mediating endocrine effects to facilitate the crosstalk between cancer cells and distant organs, as well as the interplay with nearby tumor cells. To date, the prevalence of obesity has emphasized the significance of metabolic homeostasis along with adipose tissue (AT) inflammation, cancer incidence, and multiple pathological disorders. In this review, we summarized distinct characteristics of hypertrophic adipocytes and cancer to highlight the importance of an individual's metabolic health during cancer therapy. As AT undergoes inflammatory alterations inducing tissue remodeling, immune cell infiltration, and vascularization, these features directly influence the TME by favoring tumor progression. A comparison between inflammatory AT and progressing cancer could potentially provide crucial insights into delineating the complex communication network between uncontrolled hyperplastic tumors and their microenvironmental components. In turn, the comparison will unravel the underlying properties of dynamic tumor behavior, advocating possible therapeutic targets within TME constituents.