Regulation Of Tumor Microenvironment Research Articles

High Expression of CSF-1R Predicts Poor Prognosis and CSF-1Rhigh Tumor-Associated Macrophages Inhibit Anti-Tumor Immunity in Colon Adenocarcinoma

BackgroundColony stimulating factor 1 receptor (CSF-1R) is a single channel III transmembrane receptor tyrosine kinase (RTK) and plays an important role in immune regulation and the development of various cancer types. The expression of CSF-1R in colon adenocarcinoma (COAD) and its prognostic value remain incompletely understood. Therefore, we aim to explore the prognostic value of CSF-1R in COAD and its relationship with tumor immunity.MethodsCSF-1R expression in a COAD cohort containing 103 patients was examined using immunohistochemistry (IHC). The relationship between CSF-1R expression and clinicopathological parameters and prognosis was evaluated. Dual immunofluorescence staining was conducted to determine the localization of CSF-1R in COAD tissues. Univariate and multivariate Cox regression analysis were performed to evaluate independent prognostic factors. Transcriptomic profiles of CSF-1Rhigh and CSF-1Rlow tumor-associated macrophages (TAMs) were investigated. Gene enrichment analysis was used to explore the signal pathways related to CSF-1R. In addition, the relationship between CSF-1R in tumor microenvironment (TME) and tumor immunity was also studied.ResultsIHC analysis showed that CSF-1R was overexpressed in COAD, and higher expression was associated with shorter overall survival (OS). Immunofluorescence staining showed that CSF-1R was co-localized with macrophage marker CD68. Univariate and multivariate Cox regression analysis showed that CSF-1R was an independent prognostic factor for COAD. The results of gene enrichment analysis showed that CSF-1R was involved in tumor immune response and regulation of TME. In addition, CSF-1R was significantly correlated with TME, immune cell infiltration, TMB, MSI, Neoantigen, and immune checkpoint molecules.ConclusionCSF-1R can serve as an independent prognostic factor of COAD and promising immunotherapeutic target of COAD.

GABRP is a potential prognostic biomarker and correlated with immune infiltration and tumor microenvironment in pancreatic cancer.

BackgroundPancreatic cancer is one of the most commonly diagnosed and lethal malignancies worldwide and has few good biomarkers and therapeutic targets. GABRP is the π subunit of the gamma-aminobutyric acid (GABA) A receptor, which is expressed in a number of non-neuronal tissues. GABRP is significantly upregulated in pancreatic cancer, but its biological and immunological role as well as its clinical diagnostic and prognostic value in pancreatic cancer is still incompletely known.MethodsIn this study, pancreatic adenocarcinoma (PAAD) cohorts from TCGA and GEO datasets were used to compare GABRP mRNA levels in cancerous and normal tissues and protein expression was evaluated using immunohistochemistry. The Kaplan-Meier plotter and GEPIA2 database were used to analyze the correlation between GABRP expression, overall survival, and disease-free survival in pancreatic cancer patients. Gene set enrichment analysis (GSEA) was performed with the Linked Omics database to explore the molecular mechanisms of GABRP in pancreatic cancer. And the correlation between GABRP expression and immune infiltration was explored using the TIMER database, CIBERSORT database and ESTIMATE algorithm.ResultsGABRP mRNA was significantly overexpressed in TCGA-PAAD cohorts (P<0.0001) and enhanced GABRP expression predicted poorer overall survival according to Kaplan-Meier plotter database (P=0.0024) and GEPIA2 (P=0.038). Hypomethylation of promoter (P<0.01) and the regulation of hsa-miR-3655 may contribute to the overexpression of GABRP in pancreatic cancer. GSEA analysis revealed that GABRP played an important role in the immune response. GABRP expression was also correlated with immune infiltration and immune cell markers. Higher GABRP expression was significantly associated with greater infiltration of immune cells and stromal cells into pancreatic cancer microenvironments as well as higher expression of six important immune check point genes including PDCD1 (P<0.05), CD274 (P<0.05), CTLA4 (P<0.01), PDCD1LG2 (P<0.01), TIGHT (P<0.01) and TIM3 (P<0.01).ConclusionsGABRP is a potential prognostic biomarker and is correlated with immune infiltration and tumor microenvironment in pancreatic cancer. This suggests that GABRP may serve as a potential prognostic biomarker and therapeutic target in pancreatic cancer as well as a possible regulator of tumor microenvironment affecting the efficacy of immunotherapy. Further studies are needed to elucidate the molecular mechanism of the immunoregulatory role of GABRP.

Design of the tumor microenvironment-multiresponsive nanoplatform for dual-targeting and photothermal imaging guided photothermal/photodynamic/chemodynamic cancer therapies with hypoxia improvement and GSH depletion

Due to the inherent defects of complex tumor microenvironment (TME), such as hypoxia and high glutathione (GSH) content, reactive oxygen species (ROS) mediated therapies, including photodynamic therapy (PDT) and chemodynamic therapy (CDT) are greatly limited. Ingenious design of a novel nanoplatform by improving and utilizing the TME to achieve effective antitumor effects has been a significant challenge. Herein, a TME-multiresponsive nanoplatform containing innovative photosensitizer (gold nanoclusters (Au NCs) protected by L-cysteine-polyacrylamide (LCPAA) hydrogels, magnetically targeted ferric oxide (Fe3O4) and mitochondrial localized triphenylphosphine derivatives (TPP) for cancer diagnosis and treatment is reported. The combination of Fe3O4 with Au NCs@LCPAA can broaden and enhance the near-infrared (NIR) absorption of the nanoplatform so that the considerable photothermal therapy (PTT)/PDT and photothermal imaging are achieved during NIR (808 nm) laser irradiation. More importantly, because Fe3O4 responds to acid TME and continuously decomposes into iron ions (Fe2+ & Fe3+), the Fenton reaction induced by Fe2+ ions and the production of oxygen (O2) from hydrogen peroxide (H2O2) catalyzed by Fe3+ ions as well as the depletion of GSH led by the oxidation of Fe3+ ions all can be triggered by TME rich in H2O2 and GSH, which reduce the hypoxia and antioxidant capacity of tumor so as to enhance the O2 and/or ROS-dependent PDT/CDT of Fe3O4/Au NCs@LCPAA-TPP nanoplatform. A series of in vitro and in vivo experiments have proved that through multiple regulation of TME, the as-prepared nanoplatform integrates the potential of dual-targeting, photothermal imaging as well as synergetic improved CDT/PDT/PTT.

The Combined Use of Orf Virus and PAK4 Inhibitor Exerts Anti-tumor Effect in Breast Cancer.

The parapoxvirus Orf virus (ORFV) has long been recognized as one of the valuable vectors in researches of oncolytic virus. In order to develop a potential therapeutic strategy for breast cancer based on the oncolytic virotherapy via ORFV, firstly we explore the oncolytic effects of ORFV. Our research showed that ORFV exerts anti-tumor effects in vitro by inducing breast cancer cell G2/M phase arrest and cell apoptosis. In vivo experiments were carried out, in which we treated 4T1 tumor-bearing BALB/C mice via intratumoral injection of ORFV. ORFV can exert anti-tumor activity by regulating tumor microenvironment (TME) and inducing a host immune response plus directly oncolytic effect. The CRISPR-Cas9 knockout library targeting 507 kinases was used to screen out PAK4, which is beneficial to the anti-tumor effect of ORFV on breast cancer cells. PF-3758309 is a potent PAK4-targeted inhibitor. Co-using of ORFV and PF-3758309 as a combination treatment produces its anti-tumor effects through inhibition of cell viability, induction of apoptosis and suppression of cell migration and invasion in vitro. The results of in vivo experiments showed that the tumor growth of mice in the combination treatment group was significantly inhibited, which proved that the combination treatment exerts an effective anti-tumor effect in vivo. In summary, we have clarified the oncolytic effect of ORFV on breast cancer, and found that the combination of ORFV and PAK4 inhibitor can effectively improve the oncolytic effect of ORFV. We hope our research could provide a new idea for the development of new treatment strategies for breast cancer.

The Transcription of ZIP9 Is Associated With the Macrophage Polarization and the Pathogenesis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc‐regulated transporter (ZRT)/iron‐regulated transporter (IRT) like protein transporters (ZIPs) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each ZIP involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of ZIPs in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of ZIPs between DSCs tissues and healthy controls. Notably, the transcription levels of ZIP2, ZIP5, ZIP8, ZIP9 and ZIP14 were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of Zips in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl4) inducing mouse model of HCC were established. Consistently, the mRNA levels of Zip2, Zip9, and Zip14 in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1/M2 macrophages in vitro, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of ZIPs. Our results showed that both Zip2 and Zip9 were up-regulated in M2-polarized macrophages. Zip2 transcript was also up-regulated M1-polarized macrophages, but Zip9 was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in ZIP9 transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that Zip9, but not Zip2, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, Zip9 enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/β to inhibit M1 macrophage polarization. Together, our results indicate that ZIP9 may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.

Bispecific Antibody Expressed by an Oncolytic Herpes Simplex Virus Type 2 Can Transform Heterologous T Cells Into Uniform Tumor Killer Cells.

BsAb (bispecific antibody)-armed oncolytic viruses (OVs) are effective in regulating tumor microenvironment. However, oHSV2 (oncolytic herpes simplex virus type 2) expressing immune checkpoints targeting BsAb molecules are not reported. Here, we generated oHSV2-armed PD-L1/CD3 BsAb and established pharmacodynamic evaluation models, which suggested that our oHSV2-BsAb molecules have an improved oncolytic potency in vitro and in vivo. The oHSV2 viruses armed with BsAb molecules targeting programmed cell death ligand 1 (PD-L1)/CD3 or CD19/CD3 (oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb) were constructed; besides inducing oncolysis in virus-infected tumor cells, the modified oncolytic virus oHSV2-PD-L1/CD3-BsAb can also activate peripheral blood mononuclear cells (PBMCs) by releasing PD-L1/CD3 BsAb and thereby induce PBMC-mediated killing of PD-L1-positive tumor cells, regardless of PD-L1 expression level. The expressed PD-L1/CD3 BsAb can upregulate the activation markers of T cells in PBMCs and induce different cytokine secretion. The activation of T cells and the enrichment of related immune regulatory pathways are further confirmed by proteomics. It also demonstrated that the OVs or PBMCs could upregulate PD-L1 expression on the surface of tumor cells through transforming "cold tumors" with low PD-L1 expression into "hot tumors" with high PD-L1 expression, which can facilitate the targeting of BsAb molecules and enhance the effect of oncolysis. oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb showed an enhanced oncolytic effect in vitro and in vivo compared to backbone virus oHSV2-GFP. Our results showed that the newly designed oHSV2-BsAb had enhanced therapeutic effects against solid tumors and provided a new option of immunotherapy.

Biological Hallmarks and Emerging Strategies to Target STAT3 Signaling in Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by an abnormal accumulation of plasma cells in the bone marrow. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that modulates the transcription of multiple genes to regulate various principal biological functions, for example, cell proliferation and survival, stemness, inflammation and immune responses. Aberrant STAT3 activation has been identified as a key driver of tumorigenesis in many types of cancers, including MM. Herein, we summarize the current evidence for the role of STAT3 in affecting cancer hallmark traits by: (1) sustaining MM cell survival and proliferation, (2) regulating tumor microenvironment, (3) inducing immunosuppression. We also provide an update of different strategies for targeting STAT3 in MM with special emphasis on JAK inhibitors that are currently undergoing clinical trials. Finally, we discuss the challenges and future direction of understanding STAT3 signaling in MM biology and the clinical development of STAT3 inhibitors.

Contribution of adrenergic mechanisms for the stress-induced breast cancer carcinogenesis.

Breast cancer is the most common and deadliest type of cancer in women. Stress exposure has been associated with carcinogenesis and the stress released neurotransmitters, noradrenaline and adrenaline, and their cognate receptors, can participate in the carcinogenesis process, either by regulating tumor microenvironment or by promoting systemic changes. This work intends to provide an overview of the research done in this area and try to unravel the role of adrenergic ligands in the context of breast carcinogenesis. In the initiation phase, adrenergic signaling may favor neoplastic transformation of breast epithelial cells whereas, during cancer progression, may favor the metastatic potential of breast cancer cells. Additionally, adrenergic signaling can alter the function and activity of other cells present in the tumor microenvironment towards a protumor phenotype, namely macrophages, fibroblasts, and by altering adipocyte's function. Adrenergic signaling also promotes angiogenesis and lymphangiogenesis and, systemically, may induce the formation of preneoplastic niches, cancer-associated cachexia and alterations in the immune system which contribute for the loss of quality of life of breast cancer patients and their capacity to fight cancer. Most studies points to a major contribution of β2 -adrenoceptor activated pathways on these effects. The current knowledge of the mechanistic pathways activated by β2 -adrenoceptors in physiology and pathophysiology, the availability of selective drugs approved for clinical use and a deeper knowledge of the basic cellular and molecular pathways by which adrenergic stimulation may influence cancer initiation and progression, opens the possibility to use new therapeutic alternatives to improve efficacy of breast cancer treatments.

Comprehensive Analysis and Prognosis Prediction of N6-Methyladenosine-Related lncRNAs in Immune Microenvironment Infiltration of Gastric Cancer

PurposeN6-methyladenosine (m6A) RNA modification plays an important role in regulating tumor microenvironment (TME) infiltration. However, the relationship between the expression pattern of m6A-related long non-coding RNAs (lncRNAs) and the immune microenvironment of gastric cancer (GC) is unclear.MethodsIn this study, 23 m6A-related lncRNAs were identified by Pearson’s correlation analysis and univariate Cox regression analysis. According to the expression of these lncRNAs, we identified two distinct molecular clusters by consensus clustering and compared the differences of the TME and enriched pathways between the two clusters. We further constructed a prognostic risk signature and verified it using The Cancer Genome Atlas training and testing cohorts.ResultsThe results showed that cluster 1 was associated with tumor-related and immune activation-related pathways. In addition, cluster 1 was also associated with higher ImmuneScore, StromalScore, and ESTIMATEScore. The results of the stratified survival analysis and independent prognosis analysis indicated that the risk signature is an independent prognostic indicator for patients with GC. In addition, it can effectively predict survival status in patients with different clinical characteristics. Furthermore, we found that the risk signature was associated with a variety of tumor-infiltrating immune cells, and that low risk scores were significantly correlated with high expression of programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), as well as sensitivity to chemotherapeutic drugs (eg, fluorouracil and oxaliplatin).ConclusionThis evidence contributes to our understanding of the regulation of TME infiltration by m6A-related lncRNAs and may lead to more effective immunotherapy and chemotherapy for patients with GC.

5-methylcytosine RNA methylation regulators affect prognosis and tumor microenvironment in lung adenocarcinoma.

BackgroundAccumulating evidence has shown that 5-methylcytosinec (m5C) RNA methylation plays an essential role in tumorigenesis. However, the roles of m5C regulators in the prognosis, tumor microenvironment (TME), and immunotherapy responses of lung adenocarcinoma (LUAD) have not been fully analyzed.MethodsBased on 14 m5C RNA regulators, we evaluated the m5C RNA modification patterns in patients with LUAD (n=594) in The Cancer Genome Atlas (TCGA). Unsupervised clustering analysis was performed to confirm distinct m5C modification patterns. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological functions of differentially expressed genes (DEGs) among different m5C RNA modification patterns. An m5C signature (m5Csig) was constructed using least absolute shrinkage and selection operator (LASSO) algorithms. The GSE72094 cohort (n=442) from the Gene Expression Omnibus (GEO) was used to validate m5Csig. A receiver operating characteristic (ROC) model was constructed to evaluate the sensitivity and specificity of m5Csig. Tumor-infiltrating immune cells (TIICs) between the high- and low-risk groups were estimated using the Cell Type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm.ResultsWe identified 3 m5C RNA modification clusters. Overall survival (OS) differed among the 3 clusters. The m5Csig, including TRDMT1, NSUN1, NSUN4, NSUN7, and ALYREF, was constructed to classify patients with LUAD into high- and low-risk groups. The high-risk group, with more immune cell infiltration, had a significantly poorer OS than that the low-risk group, which was associated with better response to immune checkpoint blockade therapy.ConclusionsThe present study revealed that m5C RNA regulators play a significant role in TME regulation in LUAD. The m5Csig can predict the prognosis of patients with LUAD and might provide novel strategies for tumor immunotherapy.

Light amplified oxidative stress in tumor microenvironment by carbonized hemin nanoparticles for boosting photodynamic anticancer therapy

Photodynamic therapy (PDT), which utilizes light excite photosensitizers (PSs) to generate reactive oxygen species (ROS) and consequently ablate cancer cells or diseased tissue, has attracted a great deal of attention in the last decades due to its unique advantages. However, the advancement of PDT is restricted by the inherent characteristics of PS and tumor microenvironment (TME). It is urgent to explore high-performance PSs with TME regulation capability and subsequently improve the therapeutic outcomes. Herein, we reported a newly engineered PS of polymer encapsulated carbonized hemin nanoparticles (P-CHNPs) via a facile synthesis procedure for boosting photodynamic anticancer therapy. Solvothermal treatment of hemin enabled the synthesized P-CHNPs to enhance oxidative stress in TME, which could be further amplified under light irradiation. Excellent in vitro and in vivo PDT effects were achieved due to the improved ROS (hydroxyl radicals and singlet oxygen) generation efficiency, hypoxia relief, and glutathione depletion. Moreover, the superior in vitro and in vivo biocompatibility and boosted PDT effect make the P-CHNPs a potential therapeutic agent for future translational research.

Comprehensive analysis of m6A regulator-based methylation modification patterns characterized by distinct immune profiles in colon adenocarcinomas

Mounting evidences have indicated that RNA N6-methyladenosine (m6A) modification played important roles in tumor formation and growth. However, it is rarely reported that m6A modifications are involved in the immune regulation and tumor microenvironment (TME) formation. In this study, we aimed to investigate the correlation between m6A modifications and TME regulation of colon adenocarcinoma (COAD) by bioinformatic analysis. NMF algorithm was applied to carry out consensus molecular subtype analysis on 36 selected m6A regulators regarding methylation modification, to identify m6A modification patterns and characteristics of m6A related genes in colon adenocarcinoma (COAD). Further, the relative infiltration levels of different immune cell subsets were quantified by ssGSEA and CIBERSORT algorithms, and a m6Sig scoring scheme was constructed to predict the prognosis and evaluate the response to immunotherapy in the patients with COAD. Among 579 COAD samples, we identified three different m6A modification patterns which were related to different biological pathways and clinical outcomes. Then, a scoring scheme termed “m6Sig score” was developed based on m6A-related characteristic genes, and was utilized to score patients with COAD into groups. We found that COAD patients with lower m6Sig scores exhibited prolonged survival and potentiated immune infiltration, which were associated with higher tumor mutation load, lower PD-L1 expression, and higher mutation rates of SMG (such as TTN and KRAS). Moreover, analysis regarding evaluation of immune response revealed that the patients with lower m6Sig scores had higher Immunophenoscore. Collectively, our study provided in depth insight into the interactions between m6A modification and regulation of TME. In addition, the quantitative evaluation of m6A modification patterns in our results may have implications in further immunotherapy for individual COAD patients.

Mesenchymal Stem Cells and Selenium Nanoparticles Synergize with Low Dose of Gamma Radiation to Suppress Mammary Gland Carcinogenesis via Regulation of Tumor Microenvironment

Breast cancer is one of the most prevalent and deadliest cancers among women in the world because of its aggressive behavior and inadequate response to conventional therapies. Mesenchymal stem cells (MSCs) combined with green nanomaterials could be an efficient tool in cell cancer therapy. This study examined the curative effects of bone marrow–derived mesenchymal stem cells (BM-MSCs) with selenium nanoparticles (SeNPs) coated with fermented soymilk and a low dose of gamma radiation (LDR) in DMBA-induced mammary gland carcinoma in female rats. DMBA-induced mammary gland carcinoma as marked by an elevation of mRNA level of cancer promoter genes (Serpin and MIF, LOX-1, and COL1A1) and serum level of VEGF, TNF-α, TGF-β, CA15-3, and caspase-3 with the reduction in mRNA level of suppressor gene (FST and ADRP). These deleterious effects were hampered after treatment with BM-MSCs (1 × 106 cells/rat) once and daily administration of SeNPs (20 mg/kg body weight) and exposure once to (0.25 Gy) LDR. Finally, MSCs, SeNPs, and LDR notably modulated the expression of multiple tumor promoters and suppressor genes playing a role in breast cancer induction and suppression.

Nutritional Regulation of Mammary Tumor Microenvironment

The mammary gland is a heterogeneous organ comprising of immune cells, surrounding adipose stromal cells, vascular cells, mammary epithelial, and cancer stem cells. In response to nutritional stimuli, dynamic interactions amongst these cell populations can be modulated, consequently leading to an alteration of the glandular function, physiology, and ultimately disease pathogenesis. For example, obesity, a chronic over-nutritional condition, is known to disrupt homeostasis within the mammary gland and increase risk of breast cancer development. In contrast, emerging evidence has demonstrated that fasting or caloric restriction can negatively impact mammary tumorigenesis. However, how fasting induces phenotypic and functional population differences in the mammary microenvironment is not well understood. In this review, we will provide a detailed overview on the effect of nutritional conditions (i.e., overnutrition or fasting) on the mammary gland microenvironment and its impact on mammary tumor progression.

Identification of miR-4510 as a metastasis suppressor of gastric cancer through regulation of tumor microenvironment via targeting GPC3

The genes miR-4510 and glypican-3 (GPC3) have reported to be closely associated with tumors, with miR-4510 inversely correlated with GPC3 mRNA and protein in hepatocellular carcinoma samples. Glypican-3-expressing gastric cancer (GPC3-GC), characterized as gastric cancer (GC) expressing GPC3, accounts for 11% of the GC cases. However, the expression and mechanism of action of miR-4510 in GPC3-GC have not been clearly defined. We found that miR-4510 expression in GC tissues was significantly lower than that in the adjacent tissues (p < 0.001). miRNA-4510 expression in GPC3-GC was significantly lower than that in GPC3‐negative GC tissue (p < 0.001). Our study confirmed that miR-4510 is inversely correlated with GPC3 in gastric cancer samples and that GPC3 is a direct target gene of miR-4510. The proportion of M2 macrophages in GC with low expression of miR-4510 was significantly increased, while the proliferation of CD8+ T cells was limited. miR-4510 may change the immunosuppressive signals in the tumor microenvironment by downregulating GPC3 and inhibiting gastric cancer cell metastasis. Oxaliplatin treatment may become a specific therapeutic drug for patients with miR-4510 inhibition and GPC3-GC.

Cu2-xO@TiO2-y Z-scheme heterojunctions for sonodynamic-chemodynamic combined tumor eradication

It is urgent to develop high-efficacy nanosonosensitizers with enhanced charge transfer and tumor microenvironment regulation capabilities for sonodynamic therapy (SDT). A novel heterojunction nanosonosensitizer Cu2-xO@TiO2-y was designed from core-shell oxide semiconductors with narrow bandgaps (2.1–2.2 eV) using positively charged Cu2-xO nanodots and negatively charged TiO2-y nanosheets as components. The ultrasound (US) triggered singlet oxygen (1O2) and hydroxyl radicals (•OH) generation rates notably increased compared with single components, which can be ascribed to a direct Z-scheme charge transfer mechanism that greatly improved spatial separation dynamics of US-generated electron-hole pairs. Moreover, the Cu+-Cu2+ redox cycle not only catalyzed the Fenton like reaction to generate •OH from tumor endogenous H2O2 but also depleted endogenous glutathione (GSH). Human osteosarcoma models showed complete tumor eradication by single drug injection and single US irradiation. This work highlights non-stoichiometric oxide heterostructures with the Z-scheme charge transfer mechanism for chemodynamic-sonodynamic combined therapy.

YYFZBJS inhibits colorectal tumorigenesis by enhancing Tregs-induced immunosuppression through HIF-1α mediated hypoxia in vivo and in vitro

Background and PurposeThe occurrence of colorectal cancer (CRC) is associated with a variety of factors. Accumulating evidence shows that peripheral differentiation of regulatory T cells (Tregs) is critical in controlling tumorigenesis. Our previous studies demonstrated that the Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) extract exerted potent anticancer activities by significantly enhancing immunosuppression in ApcMin/+ mice. However, there is limited knowledge on the effect of YYFZBJS in the prevention of colorectal cancer and the underlying mechanisms of action. MethodsIn this study, we investigated the effect of oral administration of YYFZBJS in preventing azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. We found that YYFZBJS treatment decreased tumor load, tumor number, histology, and the severity of disease activity index (DAI) scores. To investigate if YYFZBJS inhibited tumorigenesis by regulating regulatory T cells, we depleted Tregs in AOM/DSS mice. We then analyzed the effect of intragastric administration of YYFZBJS on tumorigenesis and the regulation of tumor microenvironment. ResultsAs expected, intragastric administration of YYFZBJS in AOM/DSS mice model significantly increased immune responses in the tumor microenvironment through its hypoxia-associated anti-cancer activities. Additionally, YYFZBJS regulated the polarization of peripheral Treg (pTreg) to suppress CRC cell proliferation and infiltration. This was demonstrated by the decrease in tumor proliferation-related proteins including p-STAT3, p-NF-κB and MMPs in a dose-dependent manner. Clinically, the increase in the levels of Tregs in human tissues during CRC progression was associated with low expression of HIF-1α in the stroma, and correlated with CRC survival and prognosis. ConclusionAltogether, we demonstrated that HIF-1α may promote pTreg -induced carcinogenesis and progression of CRC cells, indicating that YYFZBJS is a promising protective agent against HIF-1α-mediated Treg activation in colorectal cancer. This study is the first to imply a novel clinical significance of a traditional Chinese herbal medicine from Synopsis of Golden Chamber in the cancer treatment and clarify the important role of tumor microenvironment in preventing tumorigenesis.

Application of organic frame materials in cancer therapy through regulation of tumor microenvironment

During tumorigenesis and cancer progression, tumor microenvironment (TME) is continuously remodeled and a high intertumoral heterogeneity emerges due to hypoxia, oxidative stress and acidosis, etc., Recently, modulation of TME has received increasing attention for improving cancer therapy, which can solve some critical therapeutic problems such as unsatisfactory therapeutic efficiency and severe side effects. In recent years, organic framework materials (OFMs) have been designed to significantly improve cancer therapy by modulating TME, benefited from their well-organized structure, high porosity, abundant active sites, and easy post-synthetic modification. In this review, we mainly summarize the key points for fabricating OFMs with potential applications in cancer therapy, the strategies of regulating TME based on the OFMs, including the regulation of temperature, reactive oxygen species (ROS), glutathione (GSH), immune environment, gas content, and glucose concentration. The changes of TME caused by these OFMs could improve the therapeutic effect and minimize the side effects. Lastly, the existing problems and prospects of OFMs in regulating TME and improving cancer therapy are also discussed.

Erythropoietin-producing hepatocyte kinase receptor A1 facilitating the prgression of SGC-7901 cells and its transplanted tumor by increasing the expression of interleukin-6 and vascular endothelial growth factor in tumor microenvironment

Objectives Many researches showed that Erythropoietin-producing hepatocyte kinase receptor A1 (EphA1) can promote the occurrence and development of malignant tumors and may be related to tumor microenvironment. But most of them are phenomenon studies, and there are few in-depth and complete mechanism studies. This study aims to understand how EphA1 promotes the progression of malignant tumors by regulating tumor microenvironment (focusing on Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF)) from two experimental dimensions of in vitro and in vivo by using genetic engineering technology. Material and Methods We used genetic engineering technology to enhance and knock down EphA1 gene expression in SGC-7901 cells, respectively, and analyzed its influence on cell function and the expression levels of VEGF and IL-6 in cells. Subsequently, we constructed human EphA1 gene overexpression, EphA1 gene silencing, and normal expression of human EphA1 gene subcutaneous transplanted tumor models of SGC-7901 cells nude mice, and analyzed the differences in tumor development and the changes in the expression levels of VEGF and ILl-6 in tumor tissues. Results After EphA1 gene expression was enhanced, the proliferation, invasion and migration of SGC-7901 cells were enhanced, and apoptosis was weakened, and the expression levels of VEGF and IL-6 were increased. While the opposite results were found when EphA1 gene expression were knocked down. Meanwhile, tumor formation time and growth rate of subcutaneous transplantation in nude mice were advanced and the expression levels of VEGF and IL-6 in tumor tissues were increased when EphA1 gene expression were overexpressed by genetic engineering technology. Similarly, the opposite effect occurred in transplanted tumor model when EphA1 gene was silenced. Conclusion Our study showed that EphA1 can up-regulating VEGF and IL-6 expression, thereby enhancing the inflammatory environment and angiogenesis in the tumor microenvironment, and this helps to promote the progression of SGC-7901 cells and its transplanted tumor.

Transdermal Delivery System Based on Heparin Modified Graphene Oxide for Deep Transportation, Tumor Microenvironment Regulation and Immune Activation

Transdermal Delivery System Based on Heparin Modified Graphene Oxide for Deep Transportation, Tumor Microenvironment Regulation and Immune Activation