Role of the Hedgehog signaling pathway in hepatocellular carcinoma and its tumor microenvironment / 临床肝胆病杂志

The Hedgehog （Hh） signaling pathway plays an important role in the development and progression of hepatocellular carcinoma and its tumor microenvironment， and abnormal activation of Hh signal can accelerate the growth of tumor. The crosstalk between the Hh signaling pathway and TME is closely associated with tumor growth and the formation of inhibitory tumor microenvironment. Evidence shows that inhibition of Hh signal plays an important role in inhibiting the growth of hepatocellular carcinoma. This article reviews the current research status of the role， mechanism， and potential therapeutic significance of abnormal activation of Hh signal in hepatocellular carcinoma and its tumor microenvironment， so as to provide new ideas for the treatment of hepatocellular carcinoma.

Effects of hypoxia-inducible factors on tumor mesenchymal cells: a review / 预防医学

@#Hypoxia is the most common tumor microenvironment caused by rapid proliferation of tumor cells, and hypoxia-inducible factor (HIF) is the main transcription factor for tumor cells to adapt to hypoxia. Current research has found that HIF can interact with a variety of mesenchymal cells such as fibroblasts, endothelial cells and immune cells in the tumor microenvironment, leading to the transcription and expression of target genes in response to hypoxia, which ultimately promotes tumor angiogenesis, and induces physiological changes such as migration, invasion, and immune escape of tumor cells. However, the signaling pathways involved in the HIF regulatory mechanism are complex, and the mechanism of HIF in the tumor microenvironment need to be further investigated, also most HIF inhibitors are still in the preclinical research stage. This paper reviews the research progress on the effects of HIF on tumor mesenchymal stromal cells to provide a theoretical basis for the diagnosis, prevention and treatment of tumors targeting HIF.

Anti-cancer Effect of Traditional Chinese Medicine in Regulating Cellular Senescence： A Review / 中国实验方剂学杂志

In recent years， the incidence and mortality rates of cancer have been increasing， posing a serious threat to human health. Western medicine mainly uses treatments such as surgical resection， chemotherapy， immunotherapy and targeted therapy， but they are prone to complications， drug resistance and adverse reactions. A growing number of studies have shown that traditional Chinese medicine has obvious advantages in the treatment of cancer， reducing the recurrence rate of cancer and improving the quality of survival of patients. Cellular senescence refers to a state of irreversible cell cycle growth arrest when cells cease to proliferate after a limited number of divisions， resulting in a decline in cell proliferation and differentiation capacities and physiological functions， accompanied by morphological changes such as flattening and multinuclear morphology. At the molecular level， it shows increased expression of DNA damage-related genes， reduced expression of cell cycle-related factors and significant secretory activity. The malignant development of cancer is closely related to cellular senescence. With the increasing number of cancer cell proliferation， cancer-related genes undergo continuous mutations， freeing them from cellular senescence and thus achieving unlimited proliferation. Through recent studies， it has been found that induction of tumor cell senescence， possibly through modulation of cellular DNA damage， cell cycle arrest and senescence-associated secretory phenotype （SASP）， which converts the suppressive immune tumor microenvironment to an activated immune tumor microenvironment and thus reverses the escape of tumor cell senescence， is a promising strategy for cancer therapy. However， the mechanism of cellular senescence in cancer progression is not fully understood， especially the anti-cancer role played by traditional Chinese medicine in regulating cellular senescence. This article summarized and concluded the specific molecular mechanisms of cellular senescence， the role of cellular senescence in cancer progression， and the mechanism of anti-cancer effects of traditional Chinese medicine based on cellular senescence from the perspective of regulating cellular senescence， with a view to providing ideas and methods for the anti-cancer effects of traditional Chinese medicine and the development of new drugs.

Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Research progress on m5C methylation and its prospects in tumor immunotherapy / 口腔疾病防治

@#Epigenetic modification plays an important role in the biological regulatory process of eukaryotic cells. Tumor immunotherapy is an important means and clinical strategy for the treatment of some cancers. 5-Methylcytosine (m5C) is an important component of the epigenetic regulatory network discovered after m6A and has become a new topic for life science research in recent years. The m5C methylation of RNA can affect the fate of the modified RNA molecules and play an important role in various biological processes, including RNA stability, protein synthesis and transcriptional regulation. Recent studies have shown that m5C writers, erasers and readers are related to a variety of cellular biological processes and systemic diseases, including the occurrence, metastasis and tumor immune microenvironment. m5C methylation can widely affect gene expression and the biological process of tumorigenesis and development at multiple levels, but its specific mechanism and potential interaction with other epigenetic modifications in tumor immunotherapy are still unclear, and its regulatory mechanism, risk assessment and role in targeted therapy for malignant tumors need to be further studied. This article will review the dynamic regulatory network of m5C, the biological role of m5C modification in solid tumors and potential targets in tumor immunotherapy.

Research progress on mitochondria regulating anti-tumor immunity / 浙江大学学报·医学版

Tumor cells adaptively reforge their metabolism to meet the demands of energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mtROS, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We expect to explore the core role of mitochondria in the dynamic interplay between the tumor and the host, in order to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Cell-to-Cell Communications of cGAS-STING Pathway in Tumor Immune Microenvironment / 浙江大学学报·医学版

Targeting cGAS-STING pathway is a promising strategy in tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of the second messenger 2'3'-cGAMP, activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhancing the immune surveillance and inflammatory. The membrane proteins, including specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. And the ligand-receptor interactions for interferons transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment. We further explore how these mechanisms modulate immunological processes and discuss potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Deficiency in infiltration of CD8/CD3 positive lymphocytes and macrophages plays a role in lip carcinogenesis: an immunohistochemical study

Abstract Objective To evaluate the immunoexpression profile for CD8, CD3, CD20 and CD68 in the process and carcinogenesis of Carcinoma of the vermilion lip. Methods Average cell count with positive expression for CD3, CD8, CD20 and CD68. The CD8/CD3 ratio calculated in the region was based on the percentage of positive cells in a total of malignant cells. Kruska-Wallis/Dunn, Mann-Whitney and Spearman correlation tests (SPSS, p< 0.05) were used. Results In the Aquitic Cheilitis samples, there was an increase in intraepithelial CD8+ and CD68+. In LSCCs, there was an increase in peritumoral and intratumoral CD3+, CD8+, CD20+ and CD68+ cells. In peritumoral LSCC, CD3+ and CD8+ showed a direct correlation (p= 0.004), and CD68+ and CD8+ (p= 0.017). In the intraepithelial region, CD8+ correlated with CD20+ (p= 0.014) and CD68+ (p= 0.013). In the CAs, CD3 (p< 0.001) and CD8 (p= 0.025) correlated intraepithelial and subepithelial. In LSCC CD3+ (p= 0.002), CD8+ (p= 0.001) and CD68+ (p= 0.030) had intra and peritumoral correlation. Conclusion CD68+ is the first interacting cell with the greatest capacity to migrate to the tumor and interact with CD3, CD8 and CD20. Apparently, CD20 affects perineural invasion. Level of evidence: Level 2.

Elastin remodeling: Does it play a role in priming the malignant phenotype of oral mucosa?

Background: The extracellular matrix (ECM) is a dynamic tissue that provides nutrition and support to overlying epithelium. During tumorigenesis, the tumor microenvironment (TME) dysregulates the ECM. This is reflected by morphological changes seen in collagen and elastic fibers and is thought to facilitate metastasis. Aim: To study the degradation of elastic fibers in different grades of oral squamous cell carcinoma (OSCC) and in oral epithelial dysplasia (OED) using histochemistry and to correlate it to the TNM stage of OSCC. Materials and Methods: Tumor cores from 38 cases of OSCC (well-differentiated[15], moderately differentiated[14], and poorly differentiated[9]) and 15 incisional biopsies of OED were analyzed. Hematoxylin-eosin and Verhoeff's–Van Gieson (VVG) stains were used. The stained sections were assessed for morphological changes in elastic fibers. Statistical Analysis: Data were analyzed using Statistical Package for Social Sciences (SPSS) version 22 software. Fisher's exact, Kruskal–Wallis, one-way ANOVA, and Turkey post hoc tests were used to establish significance (P ? 0.05). Spearman's correlation test was used to correlate elastin fiber degradation with TNM stage of OSCC. Results: All grades of OSCC showed absence of elastic fibers around the tumor islands. Elastic fiber degradation (fragmented and clumped type fibers) increased proportionately with the grade and TNM stage of OSCC. In OED, A significant reduction in the amount of elastic fibers with increasing grade was noted. Conclusion: A positive correlation was noted between elastin degradation and grade and stage of OSCC. Therefore, it may be implicated in tumor progression of OSCC.

Multiple roles of tumor microenvironment in epithelial-mesenchymal transition of tumor cells：a review / 预防医学

@#Metastasis of tumor cells poses great difficulties for tumor therapy. Tumor microenvironment is a complex and rich multicellular environment for the development of tumors, in which tumor-associated immune cells induce tumor cells to undergo epithelial-mesenchymal transition (EMT) which enhances the invasiveness and motility of tumor cells and prompts tumor cells to metastasize, and tumor cells undergoing EMT secrete cytokines and other substances to reorganize the tumor microenvironment. The interaction between EMT and the tumor microenvironment aggravate tumor invasion and metastasis. This paper collects research literature on tumor microenvironment and EMT of tumor cells from 2015 to 2023, and reviews the role of tumor microenvironment in tumor EMT, providing the basis for research into tumor metastasis mechanism and development of anti-tumor drugs.

Analysis of immune microenvironment and potential sensitive drugs in esophageal squamous cell carcinoma based on GEO database and bioinformatics method / 中国胸心血管外科临床杂志

@#Objective    To construct a prognostic model of esophageal squamous cell carcinoma (ESCC) based on immune checkpoint-related genes and explore the potential relationship between these genes and the tumor microenvironment (TME). Methods     The transcriptome sequencing data and clinical information of immune checkpoint genes of samples from GSE53625 in GEO database were collected. The difference of gene expression between ESCC and normal paracancerous tissues was evaluated, and the drug sensitivity of differentially expressed genes in ESCC was analyzed. We then constructed a risk model based on survival-related genes and explored the prognostic characteristics, enriched pathway, immune checkpoints, immune score, immune cell infiltration, and potentially sensitive drugs of different risk groups. Results    A total of 358 samples from 179 patients were enrolled, including 179 ESCC samples and 179 corresponding paracancerous tissues. There were 33 males and 146 females, including 80 patients≤60 years and 99 patients>60 years. 39 immune checkpoint genes were differentially expressed in ESCC, including 14 low expression genes and 25 high expression genes. Drug sensitivity analysis of 8 highly expressed genes (TNFRSF8, CTLA4, TNFRSF4, CD276, TNFSF4, IDO1, CD80, TNFRSF18) showed that many compounds were sensitive to these immunotherapy targets. A risk model based on three prognostic genes (NRP1, ICOSLG, HHLA2) was constructed by the least absolute shrinkage and selection operator analysis. It was found that the overall survival time of the high-risk group was significantly lower than that of the low-risk group (P<0.001). Similar results were obtained in different ESCC subtypes. The risk score based on the immune checkpoint gene was identified as an independent prognostic factor for ESCC. Different risk groups had unique enriched pathways, immune cell infiltration, TME, and sensitive drugs. Conclusion     A prognostic model based on immune checkpoint gene is established, which can accurately stratify ESCC and provide potential sensitive drugs for ESCC with different risks, thus providing a possibility for personalized treatment of ESCC.

Preparation of CD73/PD-L1 bispecific antibody and evaluation of its antitumor function in vitro / 中国生物制品学杂志

@#Objective To prepare bispecific antibody targeting cluster of differentiation 73(CD73) and programmed cell death-ligand 1(PD-L1),and evaluate its binding ability and killing ability in vitro.Methods Using genetic engineering method,PD-L1 single-chain fragment variable(scFv) was inserted into the hinge region of CD73 monoclonal antibody to construct anti-CD73/PD-L1 bispecific antibody(BS-21),which was screened by CHO GS expression system to obtain highly expressed cell line.After purified by Protein A and molecular sieve,the purity of antibody was detected by size exclusion chromatography-high performance liquid chromatography(SEC-HPLC),the binding ability of antibody in vitro was detected by flow cytometry,and the killing ability in vitro was detected by using peripheral blood mononuclear cell(PBMC) to kill Calu 1 lung cancer cells in vitro.Results High-yield cell lines were obtained by pressure screening.A bispecific antibody BS-21 with a purity of 99.6% was obtained by purification,which bound to CD73 and PD-L1 molecules simultaneously.Compared with anti CD73 and anti PD-L1 groups,BS-21 group significantly increased the killing rate of immune cells to Calu 1 tumor cells(F=30.36,each P<0.001).Conclusion Bispecific antibody BS-21 reduced the immunosuppressive effect of CD73 and PD-Ll on immune cells simultaneously,and showed good anti-tumor function.

Progress of cellular metabolism in renal cell carcinoma and its tumor microenvironment / 肿瘤研究与临床

Renal cell carcinoma is one of the common tumors in the urinary system. Despite the high incidence of renal cell carcinoma worldwide, progress has been made in cancer control and patients' survival profits from advances in laparoscopic technology and the application of targeted drugs. Recent studies have confirmed that the progression of renal cell carcinoma is related to cellular metabolism in the tumor microenvironment. Therefore, based on the existing surgical treatment and immunotherapy, exploring new metabolic therapies that target the metabolic pathway of tumor cells and interfere with the microenvironment of tumor cells will provide a unique treatment for renal cell carcinoma.

Progress of expression and function of messenger RNA CCT6A in malignancies / 肿瘤研究与临床

Messenger RNA(mRNA) CCT6A can encode chaperone proteins and plays an important role in malignant tumors such as colorectal cancer, lung cancer and breast cancer. CCT6A is highly expressed in malignant tumors, which can be used as a biomarker to assess patients' prognosis, and promote malignant biological behaviors such as tumor proliferation and metastasis by regulating transforming growth factor β signals, cell cycles, and other pathways. CCT6A can also modulate immune cell infiltration in the tumor microenvironment and may be a potential target for tumor immunotherapy. The paper reviews the expression and function of CCT6A in malignancies.

Screening of endoplasmic reticulum stress signature-related genes in gastric cancer and the establishment of prognostic risk models / 肿瘤研究与临床

Objective:To screen the endoplasmic reticulum stress (ERS) signature-related differentially expressed genes (DEG) in gastric cancer and to construct a prognostic risk model based on a bioinformatics.Methods:Transcriptome sequencing data (RNA-seq) of 375 gastric cancer and 32 paracancerous tissue samples downloaded from The Cancer Genome Atlas (TCGA) database and the corresponding clinical information were obtained as training set samples; data of 387 gastric cancer patients (GSE84437) from Gene Expression Omnibus (GEO) database were downloaded as validation set samples. All data were obtained on December 25, 2021. A total of 785 ERS signature-related genes (ERS-RG) were obtained from the GeneCards database. DEG between gastric cancer tissues and paracancerous tissues in the TCGA database was analyzed. The identified gastric cancer DEG were intersected with ERS-RG from the GeneCards database to obtain gastric cancer ERS signature-related DEG, which were analyzed for gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Univariate Cox proportional risk model was used to screen ERS signature-related DEG with prognostic value in gastric cancer, and LASSO regression analysis was performed to construct a polygenic prognostic risk model, and to calculate the prognostic risk score. The patients in training set and validation set were divided into high-risk group and low-risk group according to the median of the prognostic risk score (2.369); Kaplan-Meier survival analysis was used to compare the overall survival (OS) and to draw time-dependent receiver operating characteristic (ROC) curves of patients in the two groups; nomogram was drawn based on the prognostic independent influencing factors of gastric cancer. The characteristic immune cell infiltration abundance between the two groups was analyzed by using the inverse convolution-based CIBERSORT algorithm. Cytolytic activity scores were calculated by using the geometric mean of granzyme A and perforin 1 expression. According to the median prognostic risk score (2.369) and median tumor mutation burden (TMB) (3.000), all patients with gastric cancer were divided into high risk score-high TMB group, high risk score-low TMB group, low risk score-high TMB group and low risk score-low TMB group to compare the OS of patients in each group.Results:A total of 444 ERS signature-related DEG in gastric cancer including 168 down-regulated genes and 276 up-regulated genes were obtained, which were mainly enriched in biological processes such as protein processing in the endoplasmic reticulum, extracellular matrix (ECM) receptor interactions and unfolded protein responses (all P < 0.05). Univariate Cox regression analysis showed that 12 prognostic-related ERS signature-related DEG in gastric cancer were screened out. LASSO regression analysis was performed to obtain a prognostic risk score = 0.052×NOS3+0.137×PON1+0.067×CXCR4+0.131×MATN3+0.116×ANXA5+0.090×SERPINE1. The results of Kaplan-Meier analysis showed that the OS of the low-risk group in both the training and validation sets was better than that of the high-risk group (all P < 0.01). The results of the time-dependent ROC curve analysis showed that the AUC for the 3-year, 5-year, 8-year OS rates was 0.695, 0.786, 0.698, respectively in the training set, while the AUC for the 3-year 5-year, 8-year OS rates was 0.580, 0.625, 0.627, respectively in the validation set. Multivariate Cox regression analysis showed that prognostic risk score ( HR = 3.598, 95% CI 2.290-5.655, P < 0.001) and tumor stage ( HR = 1.344, 95% CI 1.057-1.709, P < 0.05) were independent factors influencing the prognosis of gastric cancer. Among 375 gastric cancer patients in the TCGA database, the expression levels of ATF6, HSPA5, XBP1 and ATF4 in the high-risk group were higher than those in the low-risk group (all P < 0.05); CIBERSORT results showed that the abundance of activated CD4 memory T cells in the high-risk group was lower than that in the low-risk group, and the abundance of both M0 and M2 macrophages in the high-risk group was higher than that in the low-risk group (all P < 0.05). The expression levels of common immune checkpoints (CD274, CTLA4, TNFRSF9, TIGIT, PDCD1, LAG3) in the high-risk group were all higher than those in the low-risk group (all P < 0.05). Cytolytic activity score in the high-risk group was higher than that in the low-risk group ( P < 0.05). The prognostic risk score was negatively correlated with TMB ( r = -0.20, P < 0.001). Patients in the low-risk score-high TMB group had the best OS and those in the high-risk score-low TMB group had the worst OS (both P < 0.001). Conclusions:The prognostic risk score model is established based on 6 ERS signature-related DEG in gastric cancer and its prognostic risk score may be effective as an independent prognostic factor to predict the prognosis of gastric cancer patients.

Value of brain-expressed X-linked family genes in the diagnosis and prognosis prediction of pan-cancer / 肿瘤研究与临床

Objective:To investigate the differential expression of brain-expressed X-linked (BEX) family genes in pan-cancer and its value in diagnosis and prognosis of pan-cancer.Methods:RNA sequencing (RNA-seq) data, survival data, immune subtypes, the stem cell scores based on RNA and DNA methylation of 33 different tumors from The Cancer Genome Atlas (TCGA) database were downloaded from the online database of University of California, Santa Cruz (UCSC Xena) on April 10, 2022. The limma package of R software (V.4.2.0) was used to analyze the expression of BEX family genes in the TCGA database. The differential expression of BEX family genes in pan-cancer tissues and normal tissues was compared by using Wilcox test. Pan-cancer patients were divided into high expression group and low expression group according to the median expression level of BEX family genes; Kaplan-Meier survival analysis was used to evaluate the relationship between the expression of BEX family genes and the overall survival (OS) of patients; Cox proportional risk model was used to analyze the effect of the expression of BEX family genes on OS in pan-cancer patients and then the forest map was drawn. The correlation of the expression of BEX family genes with tumor microenviroment and tumor stem cells in pan-cancer patients was analyzed based on the correlation index Cor value. Spearman correlation analysis was used to analyze the correlation between the expression of BEX family genes and tumor microenviroment and cancer stem cell index in gastric cancer tissues. The RNA-seq of different tumor cell lines and drug sensitivity data download from the CellMiner database were used to analyze the correlation between the expression of BEX family genes and drug sensitivity. The correlation of pan-cancer and gastric cancer immune subtypes with the expression of BEX family genes was analyzed by using Kruskal test.Results:BEX3 was highly expressed in pan-cancer tissues in TCGA database, BEX2 and BEX4 were moderately expressed in pan-cancer tissues, and BEX1 and BEX5 were relatively low expressed in pan-cancer tissues. The expressions of BEX2, BEX3 and BEX4 were the highest in cholangiocarcinoma, the expression of BEX5 was the highest in endometrial neoplasms, and the expression of BEX1 was the highest in invasive breast cancer. Compared with normal tissue samples, the expressions of BEX family genes were up-regulated or down-regulated in various cancers (all P < 0.05). Survival analysis showed that the expressions of BEX family genes were associated with the OS of various cancers. Some tumor patients with high expressions of BEX1, BEX3, BEX4 and BEX5 had better OS compared with those with low expressions, and the differences were statistically significant (all P < 0.05). Other patients with high expression of BEX family genes had worse OS compared with those with low expressions, and the differences were statistically significant (all P < 0.05). Cox regression analysis showed that the high expression of BEX1 for stomach neoplasms; the high expression of BEX2 for acute myeloid leukemia, thymoma and endometrial neoplasms; the expression high of BEX3 for squamous cell carcinoma of head and neck,sarcoma, stomach neoplasms and endometrial neoplasms; the high expression of BEX4 for rectal adenocarcinoma, stomach neoplasms and endometrial neoplasms; the high expression of BEX5 for renal suspicious cell carcinoma and thymoma were risk factors for OS (all P < 0.05).The expression of BEX family genes was negatively correlated with the stromal score of most cancers (all P < 0.05), and positively correlated with the stem cell score (all P < 0.05). The expression of BEX family genes was negatively correlated with cancer stem cell index of gastric cancer ( P < 0.05), and was positively correlated with matrix score and estimated total score (all P < 0.05). Among different tumor cell lines in CellMiner database, BEX family genes were closely related to drug resistance of vemurafenib (Cor = -0.368, P = 0.004), Kahalide f (Cor = -0.391, P = 0.002), O-6-benzylguanine (Cor = -0.375, P = 0.003) and other drugs. All genes in the BEX family were related to the immune subtypes of pan-cancer and were highly expressed in C5 subtype (all P < 0.05).For gastric cancer, all genes showed high expression in the C3 subtype (all P < 0.05), except BEX5 ( P = 0.24). Conclusions:The expression of BEX family genes is closely related to the prognosis of pan-cancer patients, and has an impact on the tumor microenvironment, cancer stem cells and drug sensitivity. BEX family genes may be potential biomarkers for diagnosis and prognosis of pan-cancer.

Prognostic value of CC motif chemokine receptor 2 in the microenvironment of glioblastoma and its relationship with the immune cell infiltration / 肿瘤研究与临床

Objective:To explore the prognostic biomarkers of glioblastoma (GBM) in the tumor microenvironment (TME) and its function.Methods:A total of 169 GBM samples of 161 GBM patients were collected from the Cancer Genome Atlas (TCGA) database. ESTIMATE algorithm in R4.1.0 software was used to calculate the proportion of immune components and stromal components in TME, which were expressed as immune score and stromal score, respectively. According to the median value of the two scores, 169 GBM samples were divided into the high score group and the low score group, respectively, 84 each in each group (those whose scores were equal to the median were not involved in the grouping). The differentially expressed genes (DEG) [false discovery rate (FDR) < 0.05] between the high score group and the low score group of the two scores were obtained by using limma package, and the co-up-regulated and co-down-regulated DEG of the two scores were obtained by using Venn program. Based on the STRING database, the protein interaction (PPI) network of co-up-regulated and down-regulated DEG of immune score and stromal score was constructed, and the top 30 genes with connectivity were selected. Univariate Cox proportional hazard model analysis of overall survival (OS) of 161 GBM patients in the TCGA database was performed on co-up-regulated and down-regulated DEG between immune score and stromal score by using R4.1.0 software to obtain the DEG affecting OS. The intersection of the DEG obtained from PPI analysis and Cox analysis was taken as the prognostic core genes. According to the median expression value of prognostic core genes in GBM samples from the TCGA database, 161 patients were divided into prognostic core genes high expression group and low expression group (patients whose scores were equal to the median were not involved in the grouping), with 80 cases in each group. Kaplan-Meier survival analysis of OS was performed by using R4.1.0 software. GSEA 4.2.1 software was used to perform gene set enrichment analysis (GSEA) on all genes with transcriptome data of GBM patients in the two groups of the TCGA databases, and the main enriched functions of the two groups of genes were obtained. The CIBERSORT algorithm was used to test the accuracy of the proportion of tumor infiltrating immune cell (TIC) subsets in 169 GBM samples from the TCGA database, and 57 GBM samples were finally obtained. Immune cells with differential expression levels and immune cells related to the expression of prognostic core genes among the samples with different expression levels of prognostic core genes were analyzed; Venn program was used to obtain the intersection of immune cells with differential levels and related immune cells, and differentially expressed TIC related to expressions of prognostic core genes in GBM were obtained.Results:Based on the immune score and stromal score of GBM samples in the TCGA database, a total of 693 co-up-regulated and co-down-regulated DEG of both scores were screened out. After the intersection of 78 DEG related to OS obtained by univariate Cox regression analysis and 30 DEG obtained by PPI network results, CC motif chemokine receptor 2 (CCR2) was identified as the prognostic core gene ( HR = 1.294, 95% CI 1.060-1.579, P = 0.011). GBM patients with CCR2 high expression had worse OS compared with those with CCR2 low expression ( P = 0.009). GSEA analysis showed that genes in the CCR2 high expression group were mainly enriched in immune-related pathways, while genes in the CCR2 low expression group were mainly enriched in metabolism-related pathways. Among 57 screened GBM samples, there were differences in the levels of 3 immune cells between the CCR2 high expression group and the CCR2 low expression group ( P < 0.05). CCR2 expression was correlated with the levels of 9 immune cells (all P < 0.05). Venn program analysis showed that differentially expressed 3 TIC in GBM related to CCR2 gene expression were obtained; among them, M2 macrophages were positively correlated with CCR2 expression, while T follicular helper cell and activated NK cells were negatively correlated with CCR2 expression. Conclusions:CCR2 may be the core gene related to the prognosis in the TME of GBM. As reference, the level of CCR2 can help to predict the status of TME and prognosis in GBM patients, which is expected to provide a new direction for the treatment of GBM.

Targets of chimeric antigen receptor T-cell in breast cancer and the application progress / 肿瘤研究与临床

Breast cancer is the most common malignant tumor in women. It is particularly important to seek targeted therapy other than surgery, chemoradiotherapy, endocrine therapy. With the continuous exploration of tumor immunotherapy, more and more therapeutic targets have been discovered. This paper reviews therapeutic targets of chimeric antigen receptor T-cell (CAR-T) and the application in breast cancer.

Progress of the relationship between S100A9 and breast cancer / 肿瘤研究与临床

S100A9 is a calcium-binding protein that plays an important role in the progression of malignant tumors. Related studies have confirmed that the abnormal expression of S100A9 is closely related to the proliferation, metastasis and prognosis of breast cancer, while whether S100A9 can be used as a marker for the diagnosis and treatment of breast cancer is still controversial. This article reviews the current research status of S100A9 and its application prospect in the development, progression, diagnosis and treatment of breast cancer.