Meningioma originating from the superior petrosal vein without dural attachment: A case report.

BACKGROUND: Meningioma in the cerebellopontine angle (CPA) without dural attachment is extremely rare. We report a unique case of meningioma derived from the superior petrosal vein without dural attachment. CASE SUMMARY: A 44-year-old right-handed woman presented with a two-month history of headache and tinnitus. Brain magnetic resonance imaging showed a well-defined contrast-enhancing lesion in the right CPA without a dural tail sign. Tumor resection was performed using a right retro sigmoid approach. A dural attachment was not seen at the tentorium or posterior surface of the petrous pyramid. The tumor was firmly adherent to the superior petrosal vein. The origin site was cauterized and resected with the preservation of the superior petrosal vein. A diagnosis of meningothelial meningioma was made. The patient's headache and tinnitus gradually disappeared, and a recurrence was not observed five years after the surgery. CONCLUSION: The rare occurrence of meningioma without dural attachment makes it difficult to determine dural attachment before surgery. The absence of dural attachment makes it easy to completely resect such tumors. Vessels related to tumors should be removed carefully, considering the possible presence of tumor stem cells in the microvessels.

[Astragali Radix-Curcumae Rhizoma inhibits colon cancer progression and enhances 5-FU efficacy by regulating hypoxia-inducible factors and tumor stem cells].

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.

Development and clinical validation of a seven-gene signature based on tumor stem cell-related genes to predict ovarian cancer prognosis.

OBJECTIVE: Tumors are highly heterogeneous, and within their parenchyma, a small population of tumor-stem cells possessing differentiation potential, high oncogenicity, and self-renewal capabilities exists. These cells are pivotal in mediating tumor development, chemotherapy resistance, and recurrence. Ovarian cancer shares characteristics with tumor stem cells, making it imperative to investigate molecular markers associated with these cells. METHODS: Stem cell-related genes were collected, and molecular subtypes were established based on gene expression profiles from The Cancer Genome Atlas using the R package tool "ConsensusClusterPlus." Multi-gene prognostic markers were identified using LASSO regression analysis. Gene set enrichment analysis was employed to gain insights into the potential molecular mechanisms of these identified markers. The robustness of these prognostic markers was analyzed across different cohorts, and their clinical independence was determined through multivariate Cox analysis. A nomogram was constructed to assess the model's clinical applicability. Immunohistochemistry was performed to validate the expression of hub genes. RESULTS: Utilizing 49 tumor stem cell-related genes associated with prognosis, 362 ovarian cancer samples were divided into two distinct clusters, revealing significant prognostic disparities. A seven-gene signature (GALP, CACNA1C, COL16A1, PENK, C4BPA, PSMA2, and CXCL9), identified through LASSO regression, exhibited stability and robustness across various platforms. Multivariate Cox regression analysis confirmed the signature's independence in predicting survival in patients with ovarian cancer. Furthermore, a nomogram combining the gene signature demonstrated strong predictive abilities. Immunohistochemistry results indicated significantly elevated GALP, CACNA1C, COL16A1, PENK, C4BPA, PSMA2, and CXCL9 expression in cancer tissues. CONCLUSION: The seven-gene signature holds promise as a valuable tool for decision-making and prognosis prediction in patients with ovarian cancer.

Serine Metabolic Reprogramming in Tumorigenesis, Tumor Immunity, and Clinical Treatment.

Serine has been recently identified as an essential metabolite for oncogenesis, progression, and adaptive immunity. Influenced by many physiologic or tumor environmental factors, the metabolic pathways of serine synthesis, uptake, and usage are heterogeneously reprogrammed and frequently amplified in tumor or tumor-associated cells. The hyperactivation of serine metabolism promotes abnormal cellular nucleotide/protein/lipid synthesis, mitochondrial function, and epigenetic modifications, which drive malignant transformation, unlimited proliferation, metastasis, immunosuppression, and drug resistance of tumor cells. Dietary restriction of serine or phosphoglycerate dehydrogenase depletion mitigates tumor growth and extends the survival of tumor patients. Correspondingly, these findings triggered a boom in the development of novel therapeutic agents targeting serine metabolism. In this study, recent discoveries in the underlying mechanism and cellular function of serine metabolic reprogramming are summarized. The vital role of serine metabolism in oncogenesis, tumor stemness, tumor immunity, and therapeutic resistance is outlined. Finally, some potential tumor therapeutic concepts, strategies, and limitations of targeting the serine metabolic pathway are described in detail. Taken together, this review underscores the importance of serine metabolic reprogramming in tumorigenesis and progression and highlights new opportunities for dietary restriction or selective pharmacologic intervention.

Mechanism of Cryptotanshinone Inhibiting Proliferation of Human Breast Cancer MCF7 Cells / 肿瘤防治研究

Objective To investigate the inhibitory effect of cryptotanshinone (CPT) on human breast cancer cell MCF7 and its mechanism. Methods The survival rate of MCF7 cells was measured by MTT assay. Cell apoptosis was detected by Annexin V/PI assay and Hoechst 33258 fluorescence staining assay. Cell cycle and reactive oxygen species were detected by flow cytometry. Cell migration and invasion were detected by cell scratch test and Transwell chamber test. The surface molecules CD44 and CD24 were detected by flow cytometry and microsphere culture. The expression of cell-associated proteins was detected by Western blot. Results CPT inhibited the proliferation of MCF7 cells in a dose-dependent manner, and the 24 h IC50 value was 19.24 μmol/L. Compared with the untreated group, the CPT-treated group showed cell cycle arrested in the S phase, and apoptosis was induced. The results of the cell scratch and Transwell chamber tests showed that CPT significantly inhibited the migration and invasion of MCF7 cells. Furthermore, CPT reduced the CD24-/LowCD44+ cell population in MCF7 cell-derived microspheres. Western blot results showed that CPT could up-regulate the expression of Bax protein, down-regulate the expression of BCL-2, PI3K-p85, Akt, N-cadherin, Twist1, Sox2, Oct4, and Nanog protein, effectively inhibit the phosphorylation of ER-α, and decrease the expression of ABCG2. Conclusion CPT can inhibit the proliferation of MCF7 cells by inhibiting the migration and invasion of MCF7 cells, decreasing the number of CD24-/lowCD44+ cells and affecting the expression of tumor stem cell-related proteins.

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression.

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.

Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity.

The acquisition of genetic- and epigenetic-abnormalities during transformation has been recognized as the two fundamental factors that lead to tumorigenesis and determine the aggressive biology of tumor cells. However, there is a regularity that tumors derived from less-differentiated normal origin cells (NOCs) usually have a higher risk of vascular involvement, lymphatic and distant metastasis, which can be observed in both lymphohematopoietic malignancies and somatic cancers. Obviously, the hypothesis of genetic- and epigenetic-abnormalities is not sufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors is formed, because the cell origin of tumor is an independent factor related to tumor biology. In a given system, tumors can originate from multiple cell types, and tumor-initiating cells (TICs) can be mapped to different differentiation hierarchies of normal stem cells, suggesting that the heterogeneity of the origin of TICs is not completely chaotic. TIC's epigenome includes not only genetic- and epigenetic-abnormalities, but also established epigenetic status of genes inherited from NOCs. In reviewing previous studies, we found much evidence supporting that the status of many tumor-related "epigenetic abnormalities" in TICs is consistent with that of the corresponding NOC of the same differentiation hierarchy, suggesting that they may not be true epigenetic abnormalities. So, we speculate that the established statuses of genes that control NOC's migration, adhesion and colonization capabilities, cell-cycle quiescence, expression of drug transporters, induction of mesenchymal formation, overexpression of telomerase, and preference for glycolysis can be inherited to TICs through epigenetic memory and be manifested as their aggressive biology. TICs of different origins can maintain different degrees of innate stemness from NOC, which may explain why malignancies with stem cell phenotypes are usually more aggressive.

Expression of Insulin-Like Growth Factor Type 1 Receptor Is Linked to Inflammation in Adamantinomatous Craniopharyngioma.

INTRODUCTION: Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. METHODS: We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. RESULTS: Patients in the IGF1R high-expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate, and lower progression-free survival. ß-Catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell-like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein and decreased the transcription level of interleukin-6. CONCLUSIONS: High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor stem cell-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. IGF1R plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.

The Epigenetic Regulator Jumonji Domain-Containing Protein 6 (JMJD6) Is Highly Expressed but Not Prognostic in IDH-Wildtype Glioblastoma Patients.

Patients with IDH-wildtype glioblastoma (GBM) generally have a poor prognosis. However, there is an increasing need of novel robust biomarkers in the daily clinico-pathological setting to identify and support treatment in patients who become long-time survivors. Jumonji domain-containing protein 6 (JMJD6) is involved in epigenetic regulation of demethylation of histones and has been associated with GBM aggressiveness. We investigated the expression and prognostic potential of JMJD6 tumor fraction score in 184 IDH-wildtype GBMs. Whole-slides were double-stained with an antibody against JMJD6 and an exclusion-cocktail consisting of 4 antibodies (CD31, SMA, CD45, and Iba-1), enabling evaluation of tumor cells only. Stainings were quantified with a combined software- and scoring-based approach. For comparison, IDH-mutated WHO grade II, III and IV astrocytic gliomas were also stained, and the JMJD6 tumor fraction score increased with increasing WHO grade, although not significantly. In multivariate analysis including age, gender, performance status and post-surgical treatment high JMJD6 tumor fraction score was associated with longer overall survival in IDH-wildtype GBMs (p = 0.03), but the effect disappeared when MGMT promoter status was included (p = 0.34). We conclude that JMJD6 is highly expressed in IDH-wildtype GBM but it has no independent prognostic value.

Identification and Validation of Immune- and Stemness-Related Prognostic Signature of Melanoma.

Purpose: Our aim was to construct a signature that accurately predicted the prognostic and immune response of melanoma. Methods: First, the weighted co-expression network analysis (WGCNA) algorithm was used to identify the hub genes related to clinical phenotypes of melanoma in the cancer genome atlas (TCGA) database. Nest, the least absolute shrinkage and selection operator (LASSO) analysis was used to dimensionality reduction of these hub genes and constructed a prognostic signature to predict the prognosis and immunosuppressive response of melanoma. Result: Through in-depth analysis, we constructed a 5-mRNA prognostic signature and verified its prognostic value in internal (TCGA-SKCM, n = 452) and external independent datasets (GSE53118, n = 79). Based on this signature, the tumor immune microenvironment (TME) of melanoma was characterized, and the result was found that patients in the high-risk group had lower CD8 T cell infiltration and immune checkpoint expression (PD-1, PD-L1, CTLA4), as well as higher M0/M2 macrophage infiltration. Our results also found the risk score based on a 5-mRNA signature was significantly associated with tumor mutational burden (TMB) and tumor stem cell markers (CD20, CD38, ABCB5, CD44, etc.). Lastly, we built a nomogram for clinician prediction for the prognosis of patients with melanoma. Conclusion: Our findings indicated that the 5-mRNA signature has an important predictive value for the overall survival of melanoma. By analyzing the tumor immune microenvironment and tumor stem cell marker between different groups, a new method is provided for the stratified diagnosis and treatment of melanoma.

CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression.

The recurrence rate of lymphoma is very high, and tumor stem cells may be an important mechanism. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can inhibit antitumor immunity and promote cancer progression, but its role and mechanism in lymphoma are still unclear. Here we collected lymphoma tissue and peripheral blood from patients with diffuse large B-cell lymphoma (DLBCL). Results showed that CTLA-4 expression and CD44+ cell in the high-risk group were significantly higher than that in the low-risk group. Correlation analysis showed that CTLA-4 expression positively correlated with CD44+ cell in lymphoma tissue and regulatory T (Treg) cells in lymphocytes. In vitro experiment showed that CTLA-4 increased the ratio of lymphoma stem cells, and proliferation and invasion of lymphoma cells through TGF-ß pathway. Moreover, CTLA-4 enhanced the proliferation of Treg cells induced by lymphoma cells. Animal experiments showed that CTLA-4 can promote transplanted lymphoma growth. Immunohistochemistry results showed that both Ki-67 and CD44+ cells increased significantly in the CTLA-4 group. TGF-ß neutralization can significantly block these effects of CTLA-4. In conclusion, CTLA-4 promoted DLBCL progression through lymphoma stem cell enrichment and immunosuppression.

Brg1 is required to maintain colorectal cancer stem cells.

Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1+ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1+ intestinal tumor cells reduced intestinal tumors in ApcMin mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1+ intestinal tumor cells revealed that Brg1-null Dclk1+ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1+ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1+ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Effect of myeloid ecotropic viral integration site (MEIS) family genes on tumor microenvironment remodeling and its potential therapeutic effect.

BACKGROUND: The myeloid ecotropic viral integration site (MEIS) family of genes is related to the occurrence, development, and outcome of many cancers. However, its role in the immune and tumor microenvironment (TME) is unclear. This study explored the relationship between the expression of MEIS genes and patient survival, immune subtypes, TME, tumor stem cell correlation, and drug sensitivity in cancer. METHODS: We used The Cancer Genome Atlas pan-cancer data to analyze the expression of the MEIS family genes. Kaplan-Meier analysis and univariate Cox proportional hazard regression model were used to detect the relationship between gene expression and overall survival. Analysis of variance was used to explore the relationship between the MEIS family and the immune components in the tumor, and the ESTIMATE algorithm was used to calculate the proportion and level of tumor-infiltrating immune cells. Spearman and Pearson's correlation tests were carried out to detect the relationship between MEIS and the characteristics of tumor stem cells and drug sensitivity. RESULTS: The MEIS family of genes shows different expression profiles in different cancers, with substantial inter- and intra-cancer heterogeneity. Among them, MEIS3 was upregulated in most cancers, whereas MEIS2 was downregulated. The change in MEIS gene expression was usually related to overall survival, but whether a member of the MEIS family was a risk factor or a protective factor was cancer-dependent. Immune component analysis suggested that the role of MEIS genes in promoting or inhibiting cancer may be related to different degrees of immune silencing. Further, there were varying degrees of correlation between MEIS gene expression and cancer cell stemness characteristics. It was also found that MEIS genes, especially MEIS1 and MEIS2, may be related to chemotherapy resistance. CONCLUSIONS: We explored the expression, prognostic relationship, molecular characteristics, and effects on immunity and TME of the MEIS gene family in cancer. Our results suggest that MEIS members should be studied as independent entities in different types of cancer. The MEIS gene family may be a potential target for cancer therapy, but further experiments are needed to confirm this.

Immune profiling of pituitary tumors reveals variations in immune infiltration and checkpoint molecule expression.

PURPOSE: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. METHODS: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. RESULTS: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. CONCLUSION: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.

Influence of long non-coding RNA-CRNDE in stem cell properties and their mechanism in glioma / 中华神经医学杂志

Objective:To investigate the influence of long non-coding RNA-CRNDE in stem cell properties and their mechanism in glioma.Methods:The CD133 +U251 stem cells (U251s) were isolated from human glioma cell line U251 by immunomagnetic beads. Cells were divided into U251s group, U251s-CRNDE group, U251 group, and U251-CRNDE group; CRNDE shRNA lentiviral vectors were transfected into cells in the U251s-CRNDE group and U251-CRNDE group to down-regulate the CRNDE expression. The CRNDE mRNA expression was detected by real-time fluorescent quantitative PCR (RT-qPCR); CCK-8 assay was used to detect the cell viability; Transwell assay was used to detect the cell invasion; wound healing method was used to detect the cell migration; plate cloning assay was employed to detect the clone formation; flow cytometry was used to detect the cell cycles; Western blotting was used to detect the expressions of A2B5, CD133, nestin, Sox2, Oct-4 and Nanog, as well as phosphatidylinositol kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signal pathway key proteins (PI3K, AKT, phosphorylated-AKT, and mTOR). Results:The CRNDE mRNA expression in U251s group was significantly higher than that in U251 group ( P<0.05). As compared with U251s group, U251s-CRNDE group had significantly decreased cell viability, cell invasion and cell migration, statistically smaller number of cell colony, significantly decreased proportion of cells in G2/M phase, significantly increased proportion of cells in G1/G0 phase ( P<0.05); and the same trend was noted between U251 group and U251-CRNDE group. As compared with U251s group, U251s-CRNDE group had significantly decreased expressions of CD133, nestin, Sox2, Oct-4, PI3K, AKT, phosphorylated-AKT, and mTOR ( P<0.05). Conclusion:The CRNDE expression is increased in glioma stem cells, and down-regulation of CRNDE expression can inhibit the differentiation, metabolism and proliferation of glioma stem cells; and this effect is related to the regulation of PI3K-AKT-mTOR signaling pathway.

Strategies for Remodeling the Tumor Microenvironment Using Active Ingredients of Ginseng-A Promising Approach for Cancer Therapy.

The tumor microenvironment (TME) plays a key role in promoting the initiation and progression of tumors, leading to chemoradiotherapy resistance and immunotherapy failure. Targeting of the TME is a novel anti-tumor therapeutic approach and is currently a focus of anti-tumor research. Panax ginseng C. A. Meyer (ginseng), an ingredient of well-known traditional Asia medicines, exerts beneficial anti-tumor effects and can regulate the TME. Here, we present a systematic review that describes the current status of research efforts to elucidate the functions and mechanisms of ginseng active components (including ginsenosides and ginseng polysaccharides) for achieving TME regulation. Ginsenosides have variety effects on TME, such as Rg3, Rd and Rk3 can inhibit tumor angiogenesis; Rg3, Rh2 and M4 can regulate the function of immune cells; Rg3, Rd and Rg5 can restrain the stemness of cancer stem cells. Ginseng polysaccharides (such as red ginseng acidic polysaccharides and polysaccharides extracted from ginseng berry and ginseng leaves) can regulate TME mainly by stimulating immune cells. In addition, we propose a potential mechanistic link between ginseng-associated restoration of gut microbiota and the tumor immune microenvironment. Finally, we describe recent advances for improving ginseng efficacy, including the development of a nano-drug delivery system. Taken together, this review provides novel perspectives on potential applications for ginseng active ingredients as anti-cancer adjuvants that achieve anti-cancer effects by reshaping the tumor microenvironment.

[Silencing long non-coding RNA HIF1A-AS2 inhibits proliferation, invasion and migration of cervical cancer cells in vitro].

OBJECTIVE: To explore the inhibitory effects of silencing long non-coding RNA (LncRNA) HIF1A-AS2 on epithelialmesenchymal transition (EMT) and tumor stem cell-like phenotype in cervical cancer cells. METHODS: We designed 3 shRNA constructs for silencing HIF1A-AS2 in CaSki cells, and the shRNA with the strongest interference effect was selected for subsequent experiment. CaSki cells were transfected with shRNA-NC or Sh-HIF1A-AS2, and the changes in cell viability, invasion ability, EMT, expressions of EMT-related proteins, formation of cell spheres and expressions of stem cell markers were detected. RESULTS: Transfection with shRNA-NC and Sh-HIF1A-AS2 did not significantly affected the viability of CaSki cells (P > 0.05). Compared with the cells transfected with shRNA-NC, the cells transfected with Sh- HIF1A-AS2 showed significantly reduced invasion ability, expressions of vimentin N-cadherin, and cell sphere formation ability. HIF1A-AS2 silencing obviously lowered the rate of ABCG2-positive cells, significantly reduced the mRNA and protein expressions of Nanog, OCT4, and SOX2, and strongly enhanced the expression of E-cadherin in CaSki cells (P < 0.05). CONCLUSIONS: Silencing HIF1A-AS2 can inhibit proliferation, invasion and migration of cervical cancer cells in vitro.

UHRF2 promotes intestinal tumorigenesis through stabilization of TCF4 mediated Wnt/ß-catenin signaling.

Intestinal tumors mainly originate from transformed crypt stem cells supported by Wnt signaling, which functions through downstream critical factors enriched in the intestinal stem/progenitor compartment. Here, we show Uhrf2 is predominantly expressed in intestinal crypts and adenomas in mice and is transcriptionally regulated by Wnt signaling. Upregulated UHRF2 correlates with poor prognosis in colorectal cancer patients. Although loss of Uhrf2 did not affect intestinal homeostasis and regeneration, tumor initiation and progression were inhibited, leading to a markedly prolonged life span in Uhrf2 null mice on an ApcMin background. Uhrf2 deficiency also strongly reduced primary tumor organoid formation suggesting impairment of tumor stem cells. Moreover, ablation of Uhrf2 suppressed tumor cell proliferation through downregulation of the Wnt/ß-catenin pathway. Mechanistically, Uhrf2 directly interacts with and sumoylates Tcf4, a critical intranuclear effector of the Wnt pathway. Uhrf2 mediated SUMOylation stabilized Tcf4 and further sustained hyperactive Wnt signaling. Together, we demonstrate that Wnt-induced Uhrf2 expression promotes tumorigenesis through modulation of the stability of Tcf4 for maintaining oncogenic Wnt/ß-catenin signaling. This is a new reciprocal feedforward regulation between Uhrf2 and Wnt signaling in tumor initiation and progression.

Natural Oral Anticancer Medication in Small Ethanol Nanosomes Coated with a Natural Alkaline Polysaccharide.

Oral medication is the most acceptable therapy to treat chronic diseases. Natural drugs and excipients have unique advantages, such as low cost and high safety. We first investigated modified ethanol nanosomes for tumor treatment via oral administration. We loaded curcumin (CM) into small ethanol nanosomes coated with the natural alkaline polysaccharide chitosan (CCSET) for increased absorption and bioavailability and enhanced efficacy against small cell lung cancer (SCLC). Compared to CM and noncoated ethanol nanosomes, CCSETs exhibited superior physicochemical, in vitro-in vivo kinetic, and absorptive properties and treatment efficacy at the cellular and animal levels. The interaction of CM and serum albumin (the quantitative binding force) was analyzed. The bioavailability of CCSET increased by 11.84-fold and the tumor growth inhibition rate increased markedly compared to CM. We first confirmed the effect of CM on SCLC stem cells, and CCSET greatly enhanced this action. We first reported that CM had an antitumor effect on SCLC at the animal level and that CCSET enhanced this effect. Natural alkaline polysaccharide-coated small ethanol nanosomes delivering natural medicine may be a potential oral anticancer strategy.

Characteristics of Leiomyosarcoma: Induction of Hematogenous Metastasis by Isolated Uterine Mesenchymal Tumor Stem-like Cells.

BACKGROUND/AIM: Uterine leiomyosarcoma (Ut-LMS) is a refractory tumor that repeatedly recurs with hematogenous metastasis, which may be due to the presence of drug-resistant tumor stem cells. Its treatment is limited to surgical procedures. We previously reported that Ut-LMS spontaneously developed in mice deficient in the proteasome component low-molecular mass polypeptide 2 (LMP2). We showed that LMP2 expression was significantly attenuated specifically in human Ut-LMS. The aim of this study was to investigate the role of LMP2 in hematogenous metastasis using xenograft models with tumor stem-like cells. MATERIALS AND METHODS: We isolated tumor stem-like cells from LMP2-negative primary human Ut-LMS cells established from a human Ut-LMS tissue using the side population (SP) procedure. These cells were used to develop xenograft models with tumor stem-like cells. RESULTS: Human Ut-LMS stem-like cells showed stronger hematogenous metastatic potential than normal Ut-LMS cells. Tumor stem-like cells also had the potential to differentiate into vascular endothelial cells through VEGF-A signaling. CONCLUSION: These results reflect frequent hematogenous metastasis by human Ut-LMS in clinical settings, and may lead to the development of treatments that inhibit hematogenous metastasis in Ut-LMS.