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The tumor microenvironment (TME) plays a critical role in tumorigenesis and is comprised of different components, including tumor cells, stromal cells, and immune cells. Among them, the relationship between each mediator involved in the construction of the TME can be understood by focusing on the secreting or expressing factors from each cells. Therefore, understanding the various interactions between each cellular component of the TME is necessary for precise therapeutic approaches. In carcinoma, stromal cells are well known to influence extracellular matrix (ECM) formation and tumor progression through multiple mediators. Immune cells respond to tumor cells by causing cytotoxicity or inflammatory responses. However, they are involved in tumor escape through immunoregulatory mechanisms. In general, anti-cancer therapy has mainly been focused on cancer cells themselves or the interactions between cancer cells and specific cell components. However, cancer cells directly or indirectly influence other TME partners, and members such as stromal cells and immune cells also participate in TME organization through their mutual communication. In this review, we summarized the relationship between stromal cells and immune cells in the TME and discussed the positive and negative relationships from the point of view of tumor development for use in research applications and therapeutic strategies.

Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending on recurrence risk, intravesical chemotherapy or immunotherapy such as Bacillus Calmette–Guérin (BCG). However, persistent shortages of BCG necessitate alternative first-line treatments. We aim to use a multi-gene signature in high-risk NMIBC patients to determine whether patients may benefit from immune checkpoint inhibitors (ICIs) as an alternative to BCG and to evaluate their clinical utility. The multi-gene signature obtained from the three independent NMIBC cohorts was applied to stratify the UROMOL2016 cohort (n = 476) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis using a machine learning algorithm was performed in six independent cohorts including the BRS (n = 283) cohort treated with BCG and the IMvigor210 (n = 298) clinical trials treated with PD-L1 inhibitors. Based on consensus cluster analysis, NMIBC patients in the UROMOL2016 cohort were classified into three classes exhibiting distinguished characteristics, including DNA damage repair (DDR). Survival analysis showed that the NMIBC-DDR class had the highest rates of disease progression (progression-free survival, p = 0.002 by log-rank test) in the UROMOL cohort and benefited from BCG and ICIs (respectively, p = 0.02 and p = 0.03 by log-rank test). This study suggests that the multi-gene signature may have a role in identifying high-risk NMIBC patients and improving the responsiveness of ICIs. Additionally, we propose immunotherapy as a new first-line treatment for patients with high-risk NMIBC because of the shortage of BCG supply. It is important to help more patients prioritize cancer immunotherapy.

Diabetic retinopathy (DR) is the leading cause of vision loss and a critical complication of diabetes with a very complex etiology. The build-up of reactive oxygen species (ROS) due to hyperglycemia is recognized as a primary risk factor for DR. Although spermidine, a naturally occurring polyamine, has been reported to have antioxidant effects, its effectiveness in DR has not yet been examined. Therefore, in this study, we investigated whether spermidine could inhibit high glucose (HG)-promoted oxidative stress in human retinal pigment epithelial (RPE) cells. The results demonstrated that spermidine notably attenuated cytotoxicity and apoptosis in HG-treated RPE ARPE-19 cells, which was related to the inhibition of mitochondrial ROS production. Under HG conditions, interleukin (IL)-1β and IL-18’s release levels were markedly increased, coupled with nuclear factor kappa B (NF-κB) signaling activation. However, spermidine counteracted the HG-induced effects. Moreover, the expression of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome multiprotein complex molecules, including TXNIP, NLRP3, ASC, and caspase-1, increased in hyperglycemic ARPE-19 cells, but spermidine reversed these molecular changes. Collectively, our findings demonstrate that spermidine can protect RPE cells from HG-caused injury by reducing ROS and NF-κB/NLRP3 inflammasome pathway activation, indicating that spermidine could be a potential therapeutic compound for DR treatment.

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.

Background/Aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab.Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response.Conclusions: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid and generally found in the bark of birch trees (Betula sp.). Although several studies have been reported that BA has diverse biological activities, including anti-tumor effects, the underlying anti-cancer mechanism in bladder cancer cells is still lacking. Therefore, this study aims to investigate the anti-proliferative effect of BA in human bladder cancer cell lines T-24, UMUC-3, and 5637, and identify the underlying mechanism. Our results showed that BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest. Furthermore, BA decreased the expression of cell cycle regulators, such as cyclin B1, cyclin A, cyclin-dependent kinase (Cdk) 2, cell division cycle (Cdc) 2, and Cdc25c. In addition, BA-induced apoptosis was associated with mitochondrial dysfunction that is caused by loss of mitochondrial membrane potential, which led to the activation of mitochondrial-mediated intrinsic pathway. BA up-regulated the expression of Bcl-2-accociated X protein (Bax) and cleaved poly-ADP ribose polymerase (PARP), and subsequently activated caspase-3, -8, and -9. However, pre-treatment of pan-caspase inhibitor markedly suppressed BA-induced apoptosis. Meanwhile, BA did not affect the levels of intracellular reactive oxygen species (ROS), indicating BA-mediated apoptosis was ROS-independent. Furthermore, we found that BA suppressed the wound healing and invasion ability, and decreased the expression of Snail and Slug in T24 and 5637 cells, and matrix metalloproteinase (MMP)-9 in UMUC-3 cells. Taken together, this is the first study showing that BA suppresses the proliferation of human bladder cancer cells, which is due to induction of apoptosis, necrosis, and cell cycle arrest, and decrease of migration and invasion. Furthermore, BA-induced apoptosis is regulated by caspase-dependent and ROS-independent pathways, and these results provide the underlying anti-proliferative molecular mechanism of BA in human bladder cancer cells.

Metformin, widely used for the treatment of type 2 diabetes, has recently gained attention for its potential anticancer properties. Several studies have shown that metformin treatment inhibits cell viability in colon adenocarcinoma (COAD); however, the research related to the tumor-node-metastasis (TNM) stage is limited. As COAD is frequently diagnosed at an advanced stage, understanding the genetic factors that regulate the pathogenesis of COAD at each TNM stage and the effects of metformin for potential treatment. Therefore, we identified differentially expressed factors at the TNM stage in metformin-treated COAD cells and investigated their regulatory mechanisms using microRNAs (miRNAs). Through bioinformatics analyses, four-jointed box kinase 1 ( FJX1 ) and hsa-miR-1306-3p were identified as differentially expressed in COAD upon metformin treatment. Metformin treatment significantly reduced cell viability, with an observed decrease of approximately 50%. Analysis using quantitative real-time PCR showed an increase in hsa-miR-1306-3p and a decrease in FJX1 expression upon metformin treatment compared to untreated cells. Luciferase assay confirmed the sequence-specific binding of hsa-miR-1306-3p to FJX1 . These findings highlight the potential of metformin as a therapeutic agent for COAD by modulating FJX1 expression via upregulation of hsa-miR-1306-3p, revealing novel avenues for COAD treatment.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) mediate the degradation of acetylcholine (ACh), a primary neurotransmitter in the brain. Cholinergic deficiency occurs during the progression of Alzheimer’s disease (AD), resulting in widespread cognitive dysfunction and decline. We evaluated the potential effect of a natural cholinesterase inhibitor, zerumbone, using in vitro target enzyme assays, as well as in silico docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) simulation. Zerumbone showed a predominant cholinesterase inhibitory property with IC50 values of 2.74 ± 0.48 µM and 4.12 ± 0.42 µM for AChE and BChE, respectively; however, the modes of inhibition were different. Computational docking simulation indicated that Van der Waals interactions between zerumbone and both the cholinesterases were the main forces responsible for its inhibitory effects. Furthermore, zerumbone showed the best physicochemical properties for both bioavailability and blood–brain barrier (BBB) permeability. Together, in the present study, zerumbone was clearly identified as a unique dual AChE and BChE inhibitor with high permeability across the BBB, suggesting a strong potential for its physiological benefits and/or pharmacological efficacy in the prevention of AD.

Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K env gene was found to potentially reduce cell proliferation, cell migration, and invasion in colorectal and ovarian cancer cell lines. The immune response involves the migration and invasion of cells and is similar to cancer; however, in certain ways, it is completely unlike cancer. Therefore, we induced HERV-K119 env gene KO in THP-1, a monocytic cell that can be differentiated into a macrophage, to investigate the role of HERV-K119 env in immune regulation. Cell migration and invasion were noted to be significantly increased in HERV-K119 env KO THP-1 cells than in MOCK, and these results were contrary to those of cancer cells. To identify the underlying mechanism of HERV-K119 env KO in THP-1 cells, transcriptome analysis and cytokine array analysis were conducted. Semaphorin7A (SEMA7A), which induces the production of cytokines in macrophages and monocytic cells and plays an important role in immune effector cell activation during an inflammatory immune response, was significantly increased in HERV-K119 env KO THP-1 cells. We also found that HERV-K119 env KO THP-1 cells expressed various macrophage-specific surface markers, suggesting that KO of HERV-K119 env triggers the differentiation of THP-1 cells from monocytic cells into macrophages. In addition, analysis of the expression of M1 and M2 macrophage markers showed that M1 macrophage marker cluster of differentiation 32 (CD32) was significantly increased in HERV-K119 env KO cells. These results suggest that HERV-K119 env is implicated in the differentiation of monocytic cells into M1 macrophages and plays important roles in the immune response.

Excessive bone resorption by osteoclasts causes bone loss-related diseases and reactive oxygen species (ROS) act as second messengers in intercellular signaling pathways during osteoclast differentiation. In this study, we explored the protective effects of fermented oyster extract (FO) against receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation in murine monocyte/macrophage RAW 264.7 cells. Our results showed that FO markedly inhibited RANKL-induced activation of tartrate-resistant acid phosphatase and formation of F-actin ring structure. Mechanistically, FO has been shown to down-regulate RANKL-induced expression of osteoclast-specific markers by blocking the nuclear translocation of NF-κB and the transcriptional activation of nuclear factor of activated T cells c1 (NFATc1) and c-Fos. Furthermore, FO markedly diminished ROS production by RANKL stimulation, which was associated with blocking the expression of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) and its regulatory subunit Rac-1. However, a small interfering RNA (siRNA) targeting NOX1 suppressed RANKL-induced expression of osteoclast-specific markers and production of ROS and attenuated osteoclast differentiation as in the FO treatment group. Collectively, our findings suggest that FO has anti-osteoclastogenic potential by inactivating the NF-κB-mediated NFATc1 and c-Fos signaling pathways and inhibiting ROS generation, followed by suppression of osteoclast-specific genes. Although further studies are needed to demonstrate efficacy in in vivo animal models, FO may be used as an effective alternative agent for the prevention and treatment of osteoclastogenic bone diseases.