Trichostatin A-modified vaccine provides superior protection against ovarian cancer formation and development

More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.

Research progress on the mechanism of annexin A family members in breast cancer / 基础医学与临床

The annexins(ANX)family is widely present in the cell membrane,cytoplasm or extracellular matrix.As key tumor regulatory molecules,annexins A(ANX A)family can promote or inhibit invasion and metastasis of breast cancer cells by influencing cell membrane and cytoskeleton formation and participating in signaling pathways.ANX A family also plays a role in the apoptosis of breast cancer cells by regulation of pro-apoptotic proteins and cell cycle independent kinases(CDKs)and related pathways.In addition,ANX A family can also promote therapeutic resistance to a large number of drugs.For instance,ANX A1 enhances triple-negative breast cancer resistance by in-ducing epithelial-mesenchymal transformation.ANX A4 induces resistance by forming ANX A4-Fhit complexes and secretion of exosomes containing ANX A6 promotes paclitaxel resistance in breast cancer cells in a YAP1-dependent manner.So ANX A family may be a new target for breast cancer treatment.

Research progress of antineoplastic drugs targeting platelets / 中国药理学通报

Platelets have long been recognized as key players in hemostasis and thrombosis; however, there is growing evidence that they are also involved in cancer. Preclinical and clinical studies have shown that platelets can promote tumorigenesis and metastasis through various crosstalks between platelets and cancer cells. Platelets play an active role in all stages of tumorigenesis, including tumor growth, tumor cell extravasation, and metastasis. In addition, thrombocytosis in cancer patients is associated with poor patient survival. Platelets are also well-placed to coordinate local and distant tumor-host interactions due to the a- bundance of microparticles and exosomes. Therefore, antitumor drugs targeting platelets have great development and application prospects. The following will review the research progress of anti-tumor drugs targeting platelets.

SPP2 plays a role in the tumorigenesis of hepatocellular carcinoma:A bioinformatic based analysis / 中南大学学报(医学版)

Objective:Hepatocellular carcinoma(HCC)patients at the same stage exhibit different prognosis,and the underlying molecular mechanism remains unclear.This study aims to identify the key genes impacting the prognosis of HCC patients. Methods:Differentially expressed gene analyses were performed between HCC samples and normal ones,and between patients with long overall survival(OS)and those with short OS,in TCGA-LIHC and GSE14520 datasets.The Kaplan-Meier method with log-rank test was used to evaluate the role of secreted phosphoprotein 2(SPP2)in the prognosis of HCC patients.Gene set enrichment analysis(GSEA)was used to understand the difference of enriched signaling pathways between SPP2-stratified HCC subgroups.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses were performed to predict the potential functional pathways in which SPP2 might participate. Results:SPP2 was significantly down-regulated in tumors when compared with normal tissues,or in tumor samples with short OS when compared with those with long OS[fold change(FC)>2 and false discovery rate(FDR)<0.05].Low expression of SPP2 was associated with worse clinicopathological features like vascular invasion(P=1.6e-05),poor cancer status(with tumor,P=0.021),advanced T stage(T3 or T4,P=4.5e-04),advanced TNM stage(stage Ⅲ or Ⅳ,P=3.1e-04),and with unfavorable prognosis(shorter OS,P= 0.002).Gene enrichment analyses revealed that SPP2 might involve in the metabolic homeostasis of HCC and in the development of liver fibrosis and cirrhosis. Conclusion:SPP2 might inhibit the development of liver fibrosis and cirrhosis and the tumorigenesis of HCC,and analogs of SPP2 might be potential drugs in the prevention of these diseases.

Progress in the relationship between intestinal fungal dysbiosis and digestive system tumors / 中华微生物学和免疫学杂志

Intestinal fungal dysbiosis is closely associated with the development and progression of many diseases including tumors. The disruption of fungal communities is involved in tumorigenesis and progression through inducing aberrant host immune responses and the production of certain metabolites as well as promoting the establishment of interactions with bacteria. Fungal dysbiosis is a potential marker for early detection of digestive tumors and a factor influencing the efficacy of tumor therapy. Studying the association between gut fungi and digestive tumors may facilitate the prevention, diagnosis and treatment of digestive tumors.

Expression and clinical significance of interferon regulatory factor 4 and soluble suppression of tumorigenesis 2 in conjunctival epithelial cells and tears of patients with dry eye / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the expression and clinical significance of interferon regulatory factor 4(IRF4)and soluble suppression of tumorigenesis 2(sST2)in conjunctival epithelial cells and tears of patients with dry eye.METHODS: A total of 94 patients with dry eye who admitted to our hospital from January 2019 to December 2021 were selected as the dry eye group, and 97 physical examiners who underwent ophthalmic examination were selected as the control group at the same time. The conjunctival epithelial cells and tears of the subjects were collected, and the clinical indicators, including tear film break-up time(BUT), corneal fluorescein staining(CFS)score, and Schirmer Ⅰ test(SⅠt)were recorded. The levels of IRF4 and sST2 in conjunctival epithelial cells were detected by quantitative real-time polymerase chain reaction(qRT-PCR), and the levels of IRF4 and sST2 in tears were detected by enzyme-linked immunosorbent assay(ELISA). Pearson method was used to analyze the correlation between IRF4 and sST2 levels in conjunctival epithelial cells and tears and clinical indicators of dry eye patients.RESULTS: The levels of IRF4 and sST2 in conjunctival epithelial cells and tears in dry eye group before treatment were significantly higher than those in control group(P&#x003C;0.001). The levels of IRF4 and sST2 in conjunctival epithelial cells and tears of dry eye patients at 4wk after treatment were significantly lower than those before treatment(P&#x003C;0.001). The BUT and SⅠt of dry eye patients increased significantly at 4wk after treatment, and the CFS score decreased significantly(P&#x003C;0.001). The levels of IRF4 and sST2 in conjunctival epithelial cells and tears of dry eye patients before treatment were positively correlated with CFS score before treatment and negatively correlated with BUT and SⅠt before treatment(P&#x003C;0.001).CONCLUSION: The levels of IRF4 and sST2 in conjunctival epithelial cells and tears of patients with dry eye are increased, and are significantly correlated with BUT, SⅠt and CFS scores, which has potential to become a new therapeutic target for dry eye.

Research progress on the relationship between periodontal pathogens and colorectal cancer / 口腔疾病防治

@#With the deepening of the research on the relationship between oral microbiota and systemic diseases, researchers have found that periodontitis is closely related to diabetes, cardiovascular disease, digestive system disease and other systemic diseases. Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) are common periodontal pathogens, which play a key role in the occurrence and development of periodontitis. At present, it is also found that Fn and Pg are closely related to the occurrence and development of colorectal cancer (CRC). They can affect the occurrence and development of CRC and the therapeutic effect and prognosis of CRC patients through a variety of ways. It can promote tumor cell proliferation by regulating cell division cycle and inhibiting cell apoptosis, inhibit immune cell function to mediate immune escape and tumor metastasis, and create a pro-inflammatory microenvironment suitable for tumor survival. The study of the effect of periodontal pathogens on the occurrence and development of colorectal cancer and its mechanism also allows us to think about new methods, such as vaccine development, immune agents and antibiotic use to better prevent and treat colorectal cancer and improve the prognosis of patients with colorectal cancer.

Rac1 promotes the formation of heterotypic cell-in-cell structure / 生物工程学报

Heterotypic cell-in-cell structures (heCICs) are closely related to tumor development and progression, and have become a new frontier in life science research. Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the classic Rho GTPase, which plays a key role in regulating the cytoskeleton and cell movement. To investigate the role and mechanism of Rac1 in the formation of heCICs, tumor cells and immune killer cells were labeled with cell-tracker, respectively, to establish the heCICs model. Upon treatment with the Rac1 inhibitor NSC23766, the formation of heCICs between tumor and immune cells was significantly reduced. The plasmid pQCXIP-Rac1-EGFP constructed by gene cloning was packaged into pseudoviruses that subsequently infect tumor cells to make cell lines stably expressing Rac1. As a result, the formation of heCICs was significantly increased upon Rac1 overexpression. These results demonstrated a promotive role of Rac1 in heCICs formation, which may facilitate treating cell-in-cell related diseases, such as tumors, by targeting Rac1.

The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications

Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.

Function of Polo-like kinase 1 and its research progress in tumor therapy / 国际外科学杂志

Protein kinases are key regulators of cellular function and constitute one of the largest and participate in orch estrating the vast majority of cellular activities, forming a criss-cross regulatong network. Kinases, which play a key role in regulating the activity of cellular proteins, are prime targets for anticancer drugs because their abnormal forms can promote the proliferation of tumor cells. Polo-like kinase-1 (Plk-1) is a member of the polo-like family of serine/threonine (Ser/Thr) kinases, which is involved in many aspects of the mitotic process that regulates cell proliferation, which is one of the key kinases of cell mitosis, whose overexpression is closely related to the occurrence and development of many human cancers. Drug development targeting Plk-1 may be one of the promising directions for the treatment of cancer. This review will summarize the structural features of Plk-1 and the cellular processes involved, as well as the rationale for anti-tumor therapy against Plk-1, the latest progress in inhibitor development and the latest strategies.

Lysine Acetyltransferase 5 and Tumor / 中国生物化学与分子生物学报

Lysine acetyltransferase 5 (KAT5), a member of the MYST family, can participate in cellular processes such as transcription, DNA repair, differentiation and signal transduction by acetylating different substrates. The role of KAT5 cannot be replaced by other MYST family members, and the knockout of KAT5 can directly lead to apoptosis, indicating that KAT5 may be located in the upstream of physiological signaling pathways in cells and play an extremely important and unique role. Therefore, the changes in KAT5 expression are very likely to lead to the occurrence and development of tumors. Previous studies have found that KAT5 is downregulated in breast cancer, melanoma, and lung cancer, and is considered a tumor suppressor in these tumors. However, in recent years, studies have found that KAT5 can be either highly or lowly expressed in breast cancer, liver cancer, melanoma, prostate cancer, lung cancer and other tumors. On the premise of high KAT5 expression, KAT5 can play a tumor-promoting role. While on the premise of low KAT5 expression, KAT5 can also play as a tumor suppressor. With further decrease of KAT5 expression, its tumor suppressive effect is weakened, which may lead to the occurrence and development of tumors. In addition, KAT5 has also been found to be differentially expressed in osteosarcoma, thyroid cancer, glioblastoma, colorectal cancer and other tumors, and the differential expression of KAT5 is closely related to the proliferation, metastasis, apoptosis, drug and radiotherapy resistance of tumor cells. Therefore, KAT5 is one of the potential tumor therapeutic targets. Here, we summarize the expression of KAT5 in tumors and the tumor-suppressing or tumor-promoting signaling pathways involved in the corresponding expression in recent years, hoping to provide new inspiration and reference for tumor treatment and prognosis monitoring.

The disbalance of LRP1 and SIRPα by psychological stress dampens the clearance of tumor cells by macrophages

The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies; however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stress-evoked tumor susceptibility, and the stress hormone glucocorticoid (GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor (low-density lipoprotein receptor-related protein-1, LRP1) and the "don't eat me" signal receptor (signal regulatory protein alpha, SIRPα). Further analysis revealed that GC led to a direct, glucocorticoid receptor (GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevated gene level of SIRPα by down-regulating miRNA-4695-3p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPα axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPα axis may serve as a potential therapeutic strategy for tumor treatment.

Role and Mechanism of BDH2 Gene in Metabolism, Tumorigenesis and Progression of Cancer / 肿瘤防治研究

Cellular metabolism in tumor is an important biological process to promote the occurrence and development of tumor, and the genes related to cellular metabolism are gradually becoming the targets of tumor treatment. However, more researches are still needed to explore the abnormal metabolism in tumor progression and its prognostic value. BDH2 gene is a multifunctional gene, participates in a variety of metabolic pathways, plays an important catalytic role in iron metabolism, participates in ketone metabolism and is related to lipid metabolism. In recent years, researchers have found that BDH2 plays distinct roles in various types of tumors. The occurrence and development of a variety of tumors are closely related to BDH2. This paper analyzes, summarizes and prospects the role and mechanism of BDH2 in metabolism and tumorigenesis.

Primary cilium and its role in tumorigenesis / 浙江大学学报·医学版

The primary cilium, a sensory organelle that protrudes from the surface of most eukaryotic cells, receives and transduces various critical signals that are essential for normal development and homeostasis. Structural or functional disruption of primary cilia causes a number of human diseases, including cancer. Primary cilia has cross talks with cell cycle and it may act as a cell cycle checkpoint to suppress cancer development. Moreover, primary cilia has cross-regulation with autophagy, which may affect tumor progression. We then discuss the association of the primary cilia with several oncogenic signaling pathways, including Shh, Wnt, Notch and platelet-derived growth factor receptor (PDGFR). Since these signaling pathways are often over-activated in many types of human cancers, primary cilia are likely to play a role in the tumorigenesis by modulating these pathways. Finally, we summarize current progress on the role of cilia during tumorigenesis and the challenges that the cilia-cancer field faces.

Application and prospect of organoid culture in cancer / 中国药理学通报

At present, the traditional models for cancer research include the 2D cell model, human tumor xenograft model and animal model. With the deepening of research, the traditional tumor model is unable to meet the needs of researchers. Organoid model is derived from the surgical specimens of tumor patients, which can completely preserve the histological and genomic characteristics of tumor. It can be used in the research of tumor pathogenesis, drug screening, personalized treatment of patients, etc. Compared with traditional model, it has the advantages of short modeling time, economic benefits and closer-ness to the characteristics of the original tumor. This paper mainly focuses on the research status of organoid technology in tumor, the application of organoid model in treatment, and the advantages of organoid model compared with traditional model, so as to provide reference for the follow-up research.

Advances in understanding the role of IKKβ in tumorigenesis and its inhibitors / 中国临床药理学与治疗学

In recent years, the role of inhibitor kappa B kinaseβ (IKKβ) in the process of tumorigenesis has gradually been elucidated. IKK is involved in tumor cell proliferation and survival by acting on multiple molecular pathways. Inhibition of IKKβ has been identified as a promising treatment for cancer. Researchers have developed a series of IKKβ inhibitors and found that they can effectively inhibit tumor growth, but no IKKβ inhibitors have been used clinically to treat cancer. We discuss progress in understanding the role of IKKβ in tumorigenesis and review the recent development of main inhibitors of IKKβ.

Formation of Tumor-associated Fibroblasts and Their Role in Tumorigenesis and Development / 中国生物化学与分子生物学报

Cancer-associated fibroblasts(CAFs) are important cellular components of the tumor microenvironment. They have a variety of cellular sources, including resident fibroblasts, bone marrow mesenchymal stem cells and epithelial cells, which contribute to the development of tumors. CAFs play important roles in cancer initiation, progression, and metastasis,which can promote tumor proliferation and migration, promote tumor angiogenesis, regulate tumor immunity, and improve tumor drug resistance. Therefore, it is a promising development direction in tumor-targeted therapy. CAFs regulate the biological characteristics of tumor cells and other stromal cells through cell-to-cell contact, releases many regulatory factors and synthesizes and reshapes the extracellular matrix, and influences the occurrence and development of cancer in these ways. However, there are still many unresolved issues on the way in targeting CAFs for tumor therapy. For example, the origin and functional heterogeneity of CAFs still need to be further explored. This review mainly focuses on the summary of origin of CAFs, their roles in tumor development and the potential application in cancer targeted therapy, which will help to deepen the understanding of the roles of CAFs in cancer development and future cancer treatment.

Clinical value of sST2 in replacement of NT-proBNP in cardiac function evaluation in renal failure patients after cardiac surgery / 中国胸心血管外科临床杂志

@#Objective    To explore the clinical value of soluble suppression of tumorigenesis-2 (sST2) in replacement of N-terminal fragment of the brain natriuretic peptide precursor (NT-proBNP) in cardiac function evaluation in renal failure patients after cardiac surgery. Methods    Sixty patients with renal insufficiency after cardiac surgery from January 2019 to June 2019 were divided into a test group, including 34 males and 26 females, with an average age of 49-78 (63.3±4.5) years. Another 60 patients with normal renal function were divided into a control group, including 37 males and 23 females, with an average age of 53-77 (61.7±3.8) years. The perioperative left ventricular ejection fraction, cardiac troponin T, creatine kinase-MB, sST2 and NT-proBNP were compared. Results    In patients of the test group, the NT-proBNP level increased significantly during perioperative period, and the change range was different from other cardiac function indexes. The change of sST2 in perioperative period was similar to other cardiac function indexes, which could reflect the change degree of cardiac function after operation. Conclusion    sST2 is more important to reflect the change degree of cardiac function in patients with renal dysfunction after cardiac surgery than NT-proBNP.

3D chromatin architecture and epigenetic regulation in cancer stem cells

Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation. During this process, a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis. Such characteristics allow these cancer stem cells (CSCs) to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics. Cancer development and progression are demarcated by transcriptional dysregulation. In this article, we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation, with an emphasis on 3D chromatin architecture. Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics. We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.

Progress of TP53 Family Gene TP73 and Tumorigenesis / 肿瘤防治研究

P73 protein is one of the main members of p53 protein family, and its coding gene TP73 is highly homologous to TP53 gene. On one hand, similar to p53, p73 protein is involved in all aspects of cell life. On the other hand, unlike the p53, not only p73 protein plays the role of tumor suppressor in normal cell activities and tumor development, but also the function of p73 protein is no less complex and important than that of p53 protein. Tumorigenesis involves a variety of cellular biological processes, such as apoptosis, autophagy, cell migration and cell metabolism. These normal cellular biological processes are tightly regulated by multiple cellular signaling pathways to maintain homeostasis. Once a carcinogenic abnormality occurs, it will eventually lead to tumorigenesis. Therefore, this paper mainly focuses on the important research results of p73 and tumorigenesis and its unique function different from p53 protein in recent years.