Primary Pulmonary Meningioma With Associated Multiple Micronodules: A Case Report With Comprehensive Diagnostic Overview.

BACKGROUND: Primary pulmonary meningioma (PPM) is an exceedingly rare neoplasm originating in the meninges within the lung. Despite sharing similarities with its central nervous system (CNS) counterparts, PPM presents unique diagnostic challenges and therapeutic considerations owing to its infrequent occurrence. CASE: This case report describes a 73-year-old male who underwent chest computed tomography (CT), which revealed a mass in the posterior basal segment of the right lower lobe, suggestive of a low-grade malignant tumor approximately 30-40 mm in size. Single-port video-assisted thoracoscopic surgery (VATS) was performed to resect the mass via localized lesion excision (lung wedge resection). Intraoperative frozen section pathology indicated a low-grade malignant epithelial tumor, leading to a decision for maximal lung function preservation, considering the patient's advanced age. The surgical team opted for a localized excision to ensure negative margins. Histopathological analysis confirmed the diagnosis of epithelioid PPM, a rare subtype even among PPM cases (World Health Organization [WHO] Grade I). The patient was discharged 9 days after surgery without complications and resumed normal daily activities 1 month postoperatively. The rarity of PPM precludes a standardized treatment protocol, with surgical resection as the primary approach. However, the efficacy of adjunctive therapies remains uncertain due to limited evidence. CONCLUSION: This case report contributes to a better understanding of PPM and emphasizes the importance of a comprehensive diagnostic evaluation and individualized treatment planning for this rare entity.

Seven DNA Methylation Biomarker Prediction Models for Monitoring the Malignant Progression From Advanced Adenoma to Colorectal Cancer.

Advanced adenoma (AA) holds a significantly increased risk for progression to colorectal cancer (CRC), and we developed a noninvasive DNA methylation prediction model to monitor the risk of AA progression to CRC. We analyzed the differential methylation markers between 53 normal mucosa and 138 CRC tissues, as well as those in cfDNA (cell-free DNA) between 59 AA and 68 early-stage CRC patients. We screened the overlapping markers between tissue DNA and cfDNA for model variables and optimized the selected variables. Then, we established a cfDNA methylation prediction model (SDMBP model) containing seven methylation markers that can effectively discriminate early-stage CRC and AA in the training and validation cohorts, and the AUC (area under the curve) reached 0.979 and 0.918, respectively. Our model also reached high precision (AUC=0.938) in detecting advanced CRC (stage III/IV) and presented better performance than serum CEA and CA199 in screening CRC. The cd-score of the SDMBP model could also robustly predict the TNM stage of CRC. Overall, our SDMBP model can monitor the malignant progression from AA to CRC, and may provide a noninvasive monitoring method for high-risk populations with AA.

Expressions of EZH2 and NOTCH3 pathway in osteosarcoma and their roles in osteosarcoma stem cells.

Osteosarcoma (OS) is the most common malignant bone tumour; however, the underlying mechanisms are mainly unknown. Enhancer of zeste homologue 2 (EZH2) and NOTCH pathway are important molecular signals related to carcinogenesis and tumour progression, but they are not fully understand in OS. Enhancer of zeste homologue 2, Notch3, HES1, and Nanog were detected on OS samples and statistically analysed. Expressions of these genes were investigate, and stem-like phenotype was verified in OS cells. This study found that higher EZH2 expression, Notch3 pathway, or Nanog were associated with tumour relapse and metastasis and a significantly shorter survival time. Moreover, the Notch3 pathway was activated in osteosarcoma stem cells. Enhancer of zeste homologue 2 overexpression could activate the Notch3 pathway and increase HES1 expression, leading to upregulated stem cell-related gene expression and self-renewal of OS cells. Our study demonstrates that EZH2, Notch3, and Nanog are important prognostic factors. Enhancer of zeste homologue 2 could maintain the self-renewal of OS cells, where the Notch3 pathway activation may be involved.

Nanog promotes stem-like traits of glioblastoma cells.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor progrnosis and a high recurrence rate after surgery. To this end, we examined the role of Nanog that is highly expressed in this tumor. NANOG is a transcription factor involved in the pluripotency of embryonic stem cells (ESCs) and the induction of malignancy in cancer stem-like cells (CSCs). Bioinformatic analysis revealed that NANOG may be associated with the development of stem-like traits in GBM. Forced expression of NANOG markedly increased the expression of cancer stem cell markers and promoted the sphere formation and migration of GBM cells. Nanog enhanced the expression of SHH which is required for the maintenance of the positive feedback loop of Hedgehog signaling pathway. Treatment of GBM cells with SANT-1 and GANT61 significantly reduced the tumor progression. These data support a view that reduction of Nanog might have therapeutic benefits in GBM.

Identification of Different Form Tim-3 Proteins by a Unique Set of Tim-3 Monoclonal Antibodies.

T-cell immunoglobulin and mucin domain-3 (Tim-3) has been suggested to be a critical immune checkpoint target for cancer immunotherapy. However, limited progress with Tim-3 immunotherapy has been achieved over the last decade due to the lack of specific Tim-3 monoclonal antibodies. In this study, we have successfully developed a unique set of Tim-3 antibodies that are able to detect different molecular weights (by Western blot mobility) of Tim-3 proteins ectopically expressed in the same CHO cells. Some of the antibody clones detect only 33 or 55 kDa bands, the rest can recognize both 33 and 55 kDa bands on polyacrylamide gel electrophoresis gel. Antibody clones with 55 kDa specificity uniquely bind to the membrane form of Tim-3 on macrophage, which colocalizes with the CD68, and could be used as a specific marker for tumor-associated macrophage, whereas other clones showed cytoplasmic staining in tumor cells. The membrane form of Tim-3 on tumor-associated macrophages may bear significant roles for clinical application of Tim-3, but less likely for cytoplasmic one. The availability of this unique set of antibodies will be critical for an ultimate understanding of Tim-3 function in tumor microenvironment and potential clinical applications.

TSSC3 represses self-renewal of osteosarcoma stem cells and Nanog expression by inhibiting the Src/Akt pathway.

Osteosarcoma is the most common type of bone cancer, and the second leading cause of cancer-related death in children and young adults. Osteosarcoma stem cells are essential for osteosarcoma initiation, metastasis, chemoresistance and recurrence. In the present study, we report that: 1) higher TSSC3 expression indicates a better prognosis for osteosarcoma patients, and; 2) overexpression of TSSC3 significantly decreases sphere-forming capacity, tumor initiation, stemness-related surface markers and Nanog expression in osteosarcoma cells. We also discovered that higher Nanog expression correlates to a worse prognosis for osteosarcoma patients, and overexpression of Nanog increases the stem-related phenotype in osteosarcoma cells. Knockdown of Nanog suppresses these phenotypes. Inhibition of Nanog expression and self-renewal of osteosarcoma cells by TSSC3 overexpression appears to be mediated through inactivation of the Src/Akt pathway. In the clinical setting, expression of TSSC3, p-Src and Nanog is associated with recurrence, metastasis and surgical intervention. Lower TSSC3 expression, higher Nanog expression or higher p-Src expression indicate a poor prognosis for osteosarcoma patients. Overall, our study demonstrates that TSSC3 inhibits the stem-like phenotype and Nanog expression by inactivation of the Src/Akt pathway; this emphasizes the importance of Nanog in osteosarcoma stem cells.

RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma.

Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.

Downregulation of tumor suppressing STF cDNA 3 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by the Wnt/GSK-3ß/ß-catenin/Snail signaling pathway.

Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior of cells during cancer progression. Our previous study showed that loss of expression of TSSC3 is positively associated with osteosarcoma malignancy and progression. However, whether TSSC3 mediates EMT in osteosarcoma is poorly understood. In the present study, we determined that TSSC3 downregulation induced cell migration and invasion ability and promoted mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers and inhibiting the epithelial markers. Furthermore, TSSC3 downregulation elicited a signaling cascade that included increased levels of Wnt3a and LRP5, inactivation of GSK-3ß, accumulation of nuclear ß-catenin and Snail, the augmented binding of ß-catenin to TCF-4, and accordingly increased the expression of Wnt target genes (CD44, MMP7). The gene knockdown of these signaling proteins could inhibit TSSC3 downregulation-promoted EMT, migration, and invasion in osteosarcoma. Finally, TSSC3 overexpression obviously inhibited cell migration, invasion, and repressed mesenchymal phenotypes, reducing lung metastasis through GSK-3ß activation. Collectively, TSSC3 downregulation promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves Snail, Wnt-ß-catenin/TCF, and GSK-3ß.

The risk of new-onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants.

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta-analysis of all available case-control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448-2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large-scale studies considering gene-environment interactions and functional research should be conducted to further investigate this association.

Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets.

Osteosarcoma is the most common type of bone cancer, especially in children and young adults. The primary treatment for osteosarcoma is a combination of surgery and chemotherapy, however prognoses remain poor due to chemoresistance and early metastases. Osteosarcoma stem cells appear to play central roles in tumor recurrence, metastases and chemoresistance via self-renewal and differentiation. Targeting these cells may provide a novel strategy in the treatment of osteosarcoma. This review summarizes current knowledge of this rare phenotype and recent advances in understanding the functions OSCs (osteosarcoma stem cells) in osteosarcoma, with the aim of improving therapies in the future.

Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma.

The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3.

Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis.

The integrity of the vascular barrier, which is essential to blood vessel homoeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti-angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited using a PEDF-monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors, including adipose triglyceride lipase (ATGL) and laminin receptor (LR). Our results showed that exogenous PEDF induced vascular hyperpermeability, as measured by extravasation of Evan's Blue (EB), dextran and microspheres in the skin, blood, trachea and cremaster muscle, both in a normal state and under conditions of sepsis. In control and LR-shRNA-treated HDMECs, PEDF alone or in combination with inflammatory mediators resulted in activation of RhoA, which was accompanied by actin rearrangement and disassembly of intercellular junctions, impairing endothelial barrier function. But in ATGL-shRNA-treated HDMECs, PEDF failed to induce the aforementioned alterations, suggesting that PEDF-induced hyperpermeability was mediated through the ATGL receptor. These results reveal a novel role for PEDF as a potential vasoactive substance in septic vascular hyperpermeability. Furthermore, our results suggest that PEDF and ATGL may serve as therapeutic targets for managing vascular hyperpermeability in sepsis.

Is CD133 expression a prognostic biomarker of non-small-cell lung cancer? A systematic review and meta-analysis.

BACKGROUND: The clinical and prognostic significance of CD133 in non-small-cell lung cancer (NSCLC) remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta-analysis to evaluate the association of CD133 with prognosis and clinicopathological features of NSCLC patients. METHODS: The electronic and manual searches were performed through the database of Pubmed, Medline, Web of Science, Scopus, and Chinese CNKI (from January 1, 1982 to January 1, 2014) for titles and abstracts by using the following keywords: "CD133", "ac133" or "Prominin-1", and "lung cancer" to identify the studies eligible for our analysis. Meta-analysis was performed by using Review Manager 5.0 and the outcomes included the overall survival and various clinicopathological features. RESULTS: A total of 23 studies were finally included, and our results showed that CD133 level was significantly correlated with the overall survival (OR = 2.25, 95% CI: 1.24-4.07, P = 0.008) of NSCLC patients but not with the disease free survival (OR = 1.33, 95% CI = 0.77-2.30, P = 0.31). With respect to clinicopathological features, CD133 level was positively correlated with lymph node metastasis (OR = 1.99, 95%CI = 1.06-3.74, P = 0.03), but not correlated with the histological classification (OR = 1.00, 95%CI = 0.81-1.23, P = 0.99(ac), OR = 0.87, 95%CI = 0.61-1.24, P = 0.45(sc)), or differentiation (OR = 0.94, 95%CI 0.53-1.68, Z = 0.20, P = 0.84 random-effect) of NSCLC patients. CONCLUSION: High level of CD133 expression trends to correlate with a worse prognosis and a higher rate of lymph node metastasis in NSCLC patients, revealing CD133 as a potential pathological prognostic marker for NSCLC patients.

Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.

Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation.

[Effects of Bmi1 gene on endothelial cells promoting glioma stem cell-like phenotype].

OBJECTIVE: To explore the effects of B-cell specific Maloney leukemia virus integration site 1 (Bmi1) gene on endothelial cells promoting glioma stem cell (GSC)-like phenotype. METHODS: Glioblastoma cell line GL261 and brain micro-vessel endothelial cell line b.END3 were used. Transwell co-culture system, limit dilution assay, xenograft, real-time polymerase chain reaction (PCR), Western blot, fluorescence activating cell sorter (FACS) and gene knock-down assay were used to determine the GSC-like phenotype and Bmi1 gene expression in glioma cells. RESULTS: Compared with the control of GL261 cell alone, (1) more and larger tumor spheres formed after co-culturing with endothelial cells (62.5% ± 1.5% vs 25.0% ± 4.6% at 40 cells/well, P = 0.000). Xenografts generated by GL261 cells with b.END3 cells appeared earlier and were larger than that by GL261 cells alone ((0.798 ± 0.297) cm(3) vs (0.362 ± 0.123) cm(3), P = 0.000); (2) CD133 positive glioma cells increased after co-culturing with endothelial cells (8.48% ± 0.78% vs 4.81% ± 0.37%, P = 0.000); (3) the expression of Bmi1 in co-cultured glioma cells was up-regulated at mRNA level (2.72 ± 0.18 vs 1.00 ± 0.15, P = 0.000) and at protein level; (4) the above phenomenon was attenuated when Bmi1 gene expression was inhibited by siRNA in glioma cells, CD133 positive portion of Bmi1-knockdown GL261 cells co-culturing with b.END3 cells decreased than that of wildtype GL261 cells (0.34% ± 0.21% vs 1.70% ± 0.69%, P = 0.025). CONCLUSION: Endothelial cells promote GSC-like phenotype by up-regulating the expression of Bmi1 in glioma cells.

Glioma stem cells enhance endothelial cell migration and proliferation via the Hedgehog pathway.

The aim of the present study was to determine the possible mechanism underlying the enhanced migration and proliferation of endothelial cells caused by glioma stem cells (GSCs). Tumor spheres enriched in GSCs derived from the mouse GL261 glioma cell line, and the brain microvessel endothelial cell line, b.END3, were used in this study. A Transwell co-culture system, RNAi experiments, quantitative polymerase chain reaction, western blotting and enzyme-linked immunosorbent, cell counting kit-8 (CCK-8) proliferation, Transwell migration and wound-healing assays were used in this study to determine the migration and proliferation ability, as well as the Hedgehog (HH) pathway-related gene expression in the b.END3 cells. Based on the results, it was demonstrated that the migration and proliferation of the endothelial cells were enhanced following co-culture with GSCs. The gene expression of the HH pathway-related genes, Sonic Hedgehog (Shh) and Hedgehog-interacting protein (Hhip) was altered in the endothelial cells when co-cultured with GSCs. Overexpression of glioma-associated oncogene homolog 1 indicated activation of the HH pathway. Following knockdown of smoothened (Smo) in the endothelial cells, the migration and proliferation abilities of the cells were inhibited. GSCs have little effect on enhancing these behaviors in endothelial cells following Smo-knockdown. Further investigation revealed that Shh levels in the supernatant of the co-culture system were elevated, indicating the importance of secreted Shh from the endothelial cells. In conclusion, GSCs enhanced the migration and proliferation of the endothelial cells in vitro, which was likely associated with the activation of the HH pathway in the endothelial cells, caused by the increased secretion of Shh.