Inhibit Tumor Progression Research Articles

Abstract A025: Autotaxin-lysolipid signaling suppresses a CCL11- eosinophil axis to promote pancreatic cancer progression

Abstract Among all cancer types, pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes. In recent studies, metabolic and microenvironmental reprogramming in PDAC has been shown to facilitate tumor progression by promoting immune escape mechanisms, however these mechanisms are still poorly understood. Recently, our lab established that autotaxin (ATX) - lysophosphatidic acid (LPA) signaling in PDAC enhances tumorigenicity, but the immunomodulatory function of this signal pathway remains largely unexplored. We now show that ablation of the LPA-producing enzyme autotaxin (ATX) in PDAC cells can reduce tumor burden in mice and reprogram the tumor immune microenvironment by increasing tumor eosinophil infiltration. The functional role of eosinophils in the context of PDAC is a poorly understood area. The presence of eosinophils in pancreatic cancer has been reported in a few case reports: for example, prior studies identified neutrophils and eosinophils together as a group, expressing high levels of CD66b. We confirmed the presence of eosinophils in PDAC in mice as well as patients, and we found that rare patient samples with the highest intratumoral eosinophil abundance had the longest survival rates. Genetic or pharmacologic ATX inhibition increased intratumoral eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. When eosinophils were present, primary tumor growth was modestly reduced, but metastatic spread was greatly reduced. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop wherein ATX-LPA signaling negatively regulates activity of AP-1 transcription factor c-Jun, in turn suppressing expression of potent eosinophil chemoattractant CCL11 (Eotaxin-1). This is the first study that highlights the anti-tumor potential of eosinophils in pancreatic cancer. Citation Format: Sohinee Bhattacharyya, Chet Oon, Holly Sandborg, Terry Morgan, Mara H. Sherman. Autotaxin-lysolipid signaling suppresses a CCL11- eosinophil axis to promote pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A025.

Abstract C039: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma

Abstract Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. systemic inhibition of ADAM17 led to a reduction in tumor burden and a concomitant decrease in EGFR activation. These effects were observed exclusively in the immunocompetent animals, but not in the immunodeficient animals. It implicates that inhibition of tumor growth by MEDI3622 is highly dependent on the immune response. Furthermore, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells for tumor killing. Altogether, ADAM17 blockade displays a pronounced anti-tumor effect, suggesting ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C039.

Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis

BackgroundHepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation.MethodsBuilding upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells.ResultsSphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner.ConclusionsThis study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. Cells were separated from the single-cell RNA-sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell-cell communication. Flow cytometry, EDU staining, H3-Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF-NGFR promoting proliferation. The present study has revealed that during the process of T-cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF-NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1-mediated inhibition of unclear trans-localization of PREX1. Furthermore, PD-1 mAb acts synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF-NGFR communication was positively correlates with the PD-1/PDL-1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. Inefficiency in NGF-NGFR communication impairs PD-1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

Beauty and health: an intriguing liaison?

The exposure to different form of beauty coming from visual art, music, nature, architecture, improves mental health and exerts neurotrophic effects on different parts of the brain. This in turn improves physical health, prolongs life expectancy, and reduces the risk of serious degenerative diseases such as Alzheimer's and cancer. These beneficial actions would not be understandable and plausible if one did not accept the mind-body unity. The 'hegemonic' role of the brain in health and illness can be discerned, for example, in the effect of emotions on vital physiological parameters, in the relationships between stress and many medical-clinical pathologies, in the control exercised by the brain over the immune system reflecting also in the inhibition of tumour progression.

Autotaxin-lysolipid signaling suppresses a CCL11-eosinophil axis to promote pancreatic cancer progression.

Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX-LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX-LPA signaling in cancer.

B7–H1 agonists suppress the PI3K/AKT/mtor pathway by degrading p110γ and independently induce cell death

The biological role of B7–H1 intrinsic signal is reportedly diverse and controversial, its signal pathway remains unclear. Although B7–H1 blocking antibodies were found to have agonist capacity, their binding features and agonist mechanisms need further investigation. Here, by constructing cell strains with full-length or truncated B7–H1, we found that B7–H1 functioned as a receptor to transmit cell death signal from PD-1 protein or anti-B7-H1s through its cytoplasmic domain. Specific binding to the IgV-like domain of B7–H1 was required for the downstream signal. Upon agonists interaction, B7–H1 regulated the degradation of phosphoinositide 3-kinases (PI3Ks) subunit p110γ, subsequently inhibited the PI3K/AKT/mTOR pathway, and significantly increased autophagy. Moreover, B7–H1 agonists also suppressed ubiquitylation in B7–H1+cells by reducing ubiquitin-activating enzyme (E1), eventually leading to cell death. Finally, we validated the receptor role of B7–H1 in multiple tumor cells and demonstrated that B7–H1 agonists could suppress tumor progression independent of T cells in vivo. Our findings revealed that B7–H1 agonists functions as a PI3K inhibitor and may offer new strategies for PI3K targeting therapy.

Sanguinarine chloride induces ferroptosis by regulating ROS/BACH1/HMOX1 signaling pathway in prostate cancer

BackgroundSanguinarine chloride (S.C) is a benzophenanthrine alkaloid derived from the root of sanguinaria canadensis and other poppy-fumaria species. Studies have reported that S.C exhibits antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects, which contribute to its anti-cancer properties. Recent studies suggested that the antitumor effect of S.C through inducing ferroptosis in some cancers. Nevertheless, the precise mechanism underlying the regulation of ferroptosis by S.C remains poorly understood.MethodsA small molecule library was constructed based on FDA and CFDA approved small molecular drugs. CCK-8 assay was applied to evaluate the effects of the small molecule compound on tumor cell viability. Prostate cancer cells were treated with S.C and then the cell viability and migration ability were assessed using CCK8, colony formation and wound healing assay. Reactive oxygen species (ROS) and iron accumulation were quantified through flow cytometry analysis. The levels of malondialdehyde (MDA) and total glutathione (GSH) were measured using commercially available kits. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) among the treatment groups. Western blotting and qPCR were utilized to investigate the expression of relevant proteins and genes. In vivo experiments employed a xenograft mice model to evaluate the anti-cancer efficacy of S.C.ResultsOur study demonstrated that S.C effectively inhibited the viability of various prostate cancer cells. Notably, S.C exhibited the ability to enhance the cytotoxicity of docetaxel in DU145 cells. We found that S.C-induced cell death partially relied on the induction of ferroptosis, which was mediated through up-regulation of HMOX1 protein. Additionally, our investigation revealed that S.C treatment decreased the stability of BACH1 protein, which contributed to HMOX1expression. We further identified that S.C-induced ROS caused BACH1 instability by suppressing USP47expression. Moreover, In DU145 xenograft model, we found S.C significantly inhibited prostate cancer growth, highlighting its potential as a therapeutic strategy. Collectively, these findings provide evidence that S.C could induce regulated cell death (RCD) in prostate cancer cells and effectively inhibit tumor growth via triggering ferroptosis. This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting ROS/USP47/BACH1/HMOX1 axis.ConclusionThis study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting the ROS/USP47/BACH1/HMOX1 axis. These findings offer novel insights into the underlying mechanism by which S.C inhibits the progression of prostate cancer. Furthermore, leveraging the potential of S.C in targeting ferroptosis may present a new therapeutic opportunity for prostate cancer. This study found that S.C induces ferroptosis by targeting the ROS/USP47/BACH1/HMOX1 axis in prostate cancer cells.Graphical

Comparing the Effects of Free and Liposomal Indole Compounds on Bax and Bcl2 Gene Expression Changes in the KG-1 Cell Line

Background: For patients with acute myeloid leukemia (AML), the long-term survival rate is still very low. This study examines the effects on AML cell lines of an indole chemical in its free and liposomal forms. Material and Method: In this experimental case control study, an AML-originated KG-1 cell line was cultured in RPMI 1640 medium. The cells were treated with the free and liposomal forms of an indole compound (C18H10N2F6O) at different concentrations of 20, 40, 100, 200, and 400 µg/mL after they attained the proper confluence. The cellular metabolic activity was examined by an MTT assay. The expression of BAX and BCL-2 genes was investigated by q-PCR to assess the apoptotic effect of that compound. The analysis was also done between each experimental group and the control group using t-test. P<0.05 was assumed significant. Results: Based on the MTT assay, the lethal effective dose of free indole was found to be 245.1 µg/ml and 164.8 µg/ml in 24 and 48 hours, respectively. The corresponding values for liposomal indole were 47.2 µg/ml and 40.6 µg/ml. Furthermore, treatment with free and liposomal forms of indole resulted in a decline in the expression level of the BCL-2 gene. However, in the case of the liposomal compound, this decrease was only statistically significant after 48 hours of treatment (P < 0.05). Furthermore, the expression of BAX gene increased after treatment with both free and liposomal forms of indole, but it significantly increased only after treatment with the liposomal compound (p < 0.05). Conclusion: These results suggest that an indole derivative, especially when liposomal, causes apoptosis in AML cells, hence exhibiting cytotoxic effects. To confirm the potential usefulness of this indole derivative as a therapeutic agent for inhibiting tumor progression in the setting of human malignancies, more studies on physiologically relevant models are necessary.

Intelligent nanoreactor coupling tumor microenvironment manipulation and H2O2-dependent photothermal-chemodynamic therapy for accurate treatment of primary and metastatic tumors

Tumor microenvironment (TME), as the “soil” of tumor growth and metastasis, exhibits significant differences from normal physiological conditions. However, how to manipulate the distinctions to achieve the accurate therapy of primary and metastatic tumors is still a challenge. Herein, an innovative nanoreactor (AH@MBTF) is developed to utilize the apparent differences (copper concentration and H2O2 level) between tumor cells and normal cells to eliminate primary tumor based on H2O2-dependent photothermal-chemodynamic therapy and suppress metastatic tumor through copper complexation. This nanoreactor is constructed using functionalized MSN incorporating benzoyl thiourea (BTU), triphenylphosphine (TPP), and folic acid (FA), while being co-loaded with horseradish peroxidase (HRP) and its substrate ABTS. During therapy, the BTU moieties on AH@MBTF could capture excessive copper (highly correlated with tumor metastasis), presenting exceptional anti-metastasis activity. Simultaneously, the complexation between BTU and copper triggers the formation of cuprous ions, which further react with H2O2 to generate cytotoxic hydroxyl radical (•OH), inhibiting tumor growth via chemodynamic therapy. Additionally, the stepwise targeting of FA and TPP guides AH@MBTF to accurately accumulate in tumor mitochondria, containing abnormally high levels of H2O2. As a catalyst, HRP mediates the oxidation reaction between ABTS and H2O2 to yield activated ABTS•+. Upon 808 nm laser irradiation, the activated ABTS•+ performs tumor-specific photothermal therapy, achieving the ablation of primary tumor by raising the tissue temperature. Collectively, this intelligent nanoreactor possesses profound potential in inhibiting tumor progression and metastasis.

Immunomodulatory effects of exercise in cancer prevention and adjuvant therapy: a narrative review.

Successful application of cancer immunotherapy has rekindled hope in cancer patients. However, a number of patients are unresponsive to immunotherapy and related treatments. This unresponsiveness in cancer patients toward different treatment regimens can be mainly attributed to severe immune dysfunction in such patients. Several reports indicate that physical exercise can significantly lead to improved cancer patient outcomes. Since exercise gets immense response from the immune system, it can be utilized to improve immune function. Leukocytes with enhanced functions are substantially mobilized into the circulation by a single bout of intense physical exercise. Chronic physical exercise results in greater muscle endurance and strength and improved cardiorespiratory function. This exercise regime is also useful in improving T-cell abundance and reducing dysfunctional T cells. The current available data strongly justify for future clinical trials to investigate physical exercise use as an adjuvant in cancer therapy; however, optimal parameters using exercise for a defined outcome are yet to be established. The components of the immune system associate with almost every tumorigenesis step. The inter-relationship between inflammation, cancer, and innate immunity has recently gained acceptance; however, the underlying cellular and molecular mechanisms behind this relationship are yet to be solved. Several studies suggest physical exercise-mediated induction of immune cells to elicit anti-tumorigenic effects. This indicates the potential of exercising in modulating the behavior of immune cells to inhibit tumor progression. However, further mechanistic details behind physical exercise-driven immunomodulation and anticancer effects have to be determined. This review aims to summarize and discuss the association between physical exercise and immune function modulation and the potential of exercise as an adjuvant therapy in cancer prevention and treatment.

Shaping immune landscape of colorectal cancer by cholesterol metabolites.

Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Unveiling the multifaceted antitumor effects of interleukin 33.

Interleukin 33 (IL-33), once predominantly recognized for its pro-tumoral activities, has emerged as a multifunctional cytokine with antitumor properties. IL-33 pleiotropic activities include activation of Th1 CD4+ T cells, CD8+ T cells, NK cells, dendritic cells, eosinophils, as well as type 2 innate lymphoid cells. Regarding this immunomodulatory activity, IL-33 demonstrates synergistic interactions with various cancer therapies, including immune checkpoint blockade and chemotherapy. Combinatorial treatments leveraging IL-33 exhibit enhanced antitumor efficacy across different tumor models, promising novel avenues for cancer therapy. Despite its antitumor effects, the complex interplay of IL-33 within the tumor microenvironment underscores the need for further investigation. Understanding the mechanisms underlying IL-33's dual role as both a promoter and inhibitor of tumor progression is essential for refining therapeutic strategies and fully realizing its potential in cancer immunotherapy. This review delves into the intricate landscape of IL-33 effects within the tumor microenvironment, highlighting its pivotal role in orchestrating immune responses against cancer.

LINC01535 promotes hepatocellular carcinoma proliferation and metastasis by regulating the miR-214-3p/VASP axis.

Background: Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are associated with the development and progression of several carcinomas, including hepatocellular carcinoma (HCC). However, the role of LINC01535 in HCC is still unknown. Materials and methods: In this study, RNA-seq, CCK-8, colony formation, wound healing, Transwell and tumor xenograft assays were used to explore the function of LINC01535 in the proliferation and metastasis of HCC in vitro and in vivo. Fluorescence in situ hybridization (FISH) assay, bioinformatics analysis, dual-luciferase assay, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis were used to reveal the interactions of LINC01535, miR-214-3p and VASP. Results: LINC01535 was overexpressed in HCC tissues and HCC cell lines. Gain- and loss-of-function studies revealed that LINC01535 could promote HCC cell proliferation, migration and invasion both in vitro and in vivo. In addition, upregulation of LINC01535 significantly decreased the expression of microRNA-214-3p (miR-214-3p), which was found closely associated with suppressing tumor progression. Moreover, VASP was identified as a direct downstream target gene of miR-214-3p. LINC01535 positively regulated VASP expression by sponging miR-214-3p, and VASP overexpression activated the PI3K/AKT signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT) in HCC. Conclusions: Our study first found that LINC01535 promoted HCC progression by regulating its downstream target, the miR-214-3p/VASP axis, via the PI3K/AKT signaling pathway. The function and novel regulatory mechanism of LINC01535 may provide a valuable target for the diagnosis and treatment of HCC patients.

A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.

Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

Aspirin Inhibits Colorectal Cancer via the TIGIT-BCL2-BAX pathway in T Cells.

The T cell immunoglobulin and ITAM domain (TIGIT) is a recently discovered synergistic co-suppressor molecule that plays an important role in immune response and tumor immune escape in the context of cancer. Importantly, CD155 acts as a receptor for TIGIT, and CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. Aspirin (ASA) has been shown to reduce the growth and survival of colorectal cancer (CRC) cells, but the immunological mechanisms involved have not been sufficiently elucidated. In the present study the effects of aspirin on CRC in mice and on Jurkat cells were investigated. Aspirin may suppress the expression of TIGIT on T cells and Regulatory T cells (Tregs) and inhibit T cell viability, and therefore induce tumor cell apoptosis. TIGIT is expressed at higher levels on infiltrating lymphocytes within CRC tumor tissue than adjacent. Further, aspirin could inhibit Jurkat cell proliferation and induce apoptosis via downregulation of TIGIT expression and the anti-apoptosis B cell lymphoma 2 (BCL2) protein and upregulation of BCL2-associated X protein (BAX) expression. The present study suggests that aspirin can inhibit specific aspects of T cell function by reducing interleukin-10 and transforming growth factor-β1 secretion via the TIGIT-BCL2-BAX signaling pathway, resulting in improved effector T cell function that inhibits tumor progression.

Long noncoding RNA lnc-SNAPC5-3:4 inhibits malignancy by directly upregulating miR-224-3p in non-small cell lung cancer

The mounting body of evidence demonstrates the growing importance of long noncoding RNAs in the advancement of tumors. This study aimed to investigate the molecular mechanism of lnc-SNAPC5-3:4 in non-small cell lung cancer (NSCLC). We investigated the expression of miR-224-3p and lnc-SNAPC5-3:4 in clinical NSCLC samples and NSCLC cell lines using reverse transcription polymerase chain reaction (RT-PCR). In vitro studies, A549 cell growth was estimated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EDU), and flow cytometry assays. In vivo studies, NSCLC tumorigenesis was determined using xenograft tumor mouse models, tumor growth was evaluated using antigen Kiel 67 (Ki67) staining, and tumor apoptosis was detected through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The relationship between lnc-SNAPC5-3:4 and miR-224-3p was determined by luciferase reporter gene assay. Results indicated that the expression of lnc-SNAPC5-3:4 was observed to be downregulated in NSCLC tissues and cell lines. After overexpression of lnc-SNAPC5-3:4 in cultured A549 cells, proliferation decreased and apoptosis increased. Furthermore, the expression of miR-224-3p was targeted and negatively regulated by lnc-SNAPC5-3:4. The lnc-SNAPC5-3:4 upregulation inhibited cell proliferation and promoted apoptosis, which was partially blocked by miR-224-3p overexpression in A549 cells. In addition, we constructed a subcutaneous inoculation model using BALB/c nude mice, and the results indicated that lnc-SNAPC5-3:4 overexpression restrained the growth of subcutaneous tumors, decreased Ki67 expression levels, and increased apoptosis, as indicated by TUNEL staining in nude mice. However, miR-224-3p transfection resulted in the reversal of the inhibitory effect of lnc-SNAPC5-3:4 on tumor growth. In conclusion, our study revealed that lnc-SNAPC5-3:4 inhibits tumor progression in NSCLC by targeting miR-224-3p. This study provides a potential therapeutic target for inhibiting NSCLC progression.

An arabinose-rich heteropolysaccharide isolated from Belamcanda chinensis (L.) DC treats liver cancer by targeting FAK and activating CD40

An undisclosed polysaccharide, BCP80–2, was isolated from Belamcanda chinensis (L.) DC. Structural investigation revealed that BCP80–2 consists of ten monosaccharide residues including t-α-Araf-(1→, →3,5)-α-Araf-(1→, →5)-α-Araf-(1→, →4)-β-Xylp-(1→, →3)-α-Rhap-(1→, →4)-β-Manp-(1→, t-β-Glcp-(1→, →6)-α-Glcp-(1→, t-β-Galp-(1→, and→3)-α-Galp-(1→. In vivo activity assays showed that BCP80–2 significantly suppressed neoplasmic growth, metastasis, and angiogenesis in zebrafish. Mechanistic studies have shown that BCP80–2 inhibited cell migration of HepG2 cells by suppressing the FAK signaling pathway. Moreover, BCP80–2 also activated immunomodulation and upregulated the secretion of co-stimulatory molecules CD40, CD86, CD80, and MHC-II. In conclusion, BCP80–2 inhibited tumor progression by targeting the FAK signaling pathway and activating CD40-induced adaptive immunity.

ITM2A inhibits the progression of bladder cancer by downregulating the phosphorylation of STAT3.

Bladder cancer stands as one of the prevalent malignancies in urological clinics, highlighting the pressing need to uncover prognostic or therapeutic avenues. ITM2A, a transmembrane protein, has been identified as a suppressor in tumor progression recently. Our study underscored a significant correlation between low ITM2A expression in bladder cancer tissues and high tumor grade, AJCC stage, and poor overall survival time. Additionally, our findings demonstrated that reinstating ITM2A expression impeded cell proliferation, migration, and invasion, while conversely, its suppression enhanced these malignant behaviors. Furthermore, we elucidated that ITM2A could suppress malignant phenotypes of bladder cancer cells via inhibiting activation of the STAT3 induced by IL-6. In conclusion, our research unveiled the mechanistic role of ITM2A in inhibiting tumor progression, shedding light on its potential as a prognostic predictor and therapeutic target in bladder cancer management.

Unraveling the Action Mechanism of Tubeimoside-1 against Tumor Microvessels via Network Pharmacology and Experimental Validation.

Objective: Tubeimoside-1 (TBMS1) is a plant-derived triterpenoid saponin that exhibits pharmacological properties and anti-tumor effects, but the anti-tumor microvessels of action of TBMS1 remains to be completely elucidated. This study aims to verify the effect of TBMS1 on tumor microvessels and its underlying mechanism. Methods: A SKOV3 xenografted mouse model were constructed to evaluate the anti-tumor microvessels of TBMS1 in vivo, followed by function assays to verify the effects of TBMS1 on the proliferation, cell cycle, migration, and tubule formation of vascular endothelial cells in vitro. Next, based on network pharmacology, the drug/disease-target protein-protein interaction (PPI) networks, biological functions and gene enrichment analyses were performed to predict the underlying mechanism. Finally, molecules and pathways associated with tumor trans-endothelial migration were identified. Results: TBMS1 treatment effectively reduced tumor microvessel density in ovarian cancer model and inhibited the proliferation, cell cycle, migration, and induced apoptosis of vascular endothelial cells in vitro. Network pharmacological data suggested that tumor cell adhesion and trans-endothelial migration may participate in antiangiogenic effects of TBMS1. By endothelial adhesion and permeability assay, we identified that tumor adhesion and the permeability of endothelial monolayers were reduced by TBMS1. Furthermore, adhesion protein (VCAM-1and ICAM-1) and tight junction (TJ) proteins (VE-cadhsion, ZO-1 and claudin-5) were found to be regulated. Finally, Akt, Erk1/2, Stat3 and NF-κB signaling were decreased by TBMS1 treatment. Conclusion: To sum up, our findings strongly suggest that clinical application of TBSM1 may serve as a vasoactive drug treatment to suppress tumor progression.