An Acid Response IR780-Based Targeted Nanoparticle for Intraoperative Near-Infrared Fluorescence Imaging of Ovarian Cancer.

Introduction: Complete resection of all visible disease (R0 resection) is critical for the treatment of ovarian cancer patients, and accurate real-time guidance provided by intraoperative near-infrared (NIR) fluorescence images is beneficial for achieving complete resection of all visible disease. Methods: Based on the optical properties of IR780 and the characteristics of the acidic tumor microenvironment, we develop a new smart nanoparticle (eg, FA-IR780&PFOB-SNPs) by using the pH response nano framework (FA-PEG-PLGA-PEOz) and adjusting the amount of IR780. The FA-IR780&PFOB-SNPs was characterized for morphology, microstructure, particle size, pH-response, drug-loading efficiency and biological safety. The ultraclear fluorescence Navigation Endoscopy System was applied to evaluate the tumor recognition of FA-IR780&PFOB-SNPs in vivo. Results: The structure of FA-IR780&PFOB-SNPs was stable in a neutral environment, and the near-infrared (NIR) fluorescence was turned off, while the structure of FA-IR780&PFOB-SNPs was degraded in the acidic tumour microenvironment, and the NIR fluorescence was turned on. Through the ovarian subcutaneous xenograft tumour and ovarian intraperitoneal xenograft tumour models, it was confirmed that FA-IR780&PFOB-SNPs could clearly display the boundaries of abdominal micron-sized tumours through near-infrared fluorescence imaging, with a TBR greater than 5. Conclusion: The FA-IR780&PFOB-SNPs have the potential to provide to ovarian cancer intraoperative near infrared fluorescence navigation during precision tumour resection to achieve R0 and improve the prognosis of ovarian cancer patients.

Overexpression of CAPG Is Associated with Poor Prognosis and Immunosuppressive Cell Infiltration in Ovarian Cancer.

Historically, immunotherapies have only resulted in a partial response from patients with advanced ovarian cancer, resulting in poor clinical efficacy. A full understanding of immune-related gene expression and immunocyte infiltration in ovarian cancer would be instrumental for the improved implementation of immunotherapy. The Capping Actin Protein, Gelsolin-Like (CAPG) gene encodes an actin-regulatory protein, which plays important roles in tumor progression and immune regulation. This study is aimed at identifying the potential therapeutic and prognostic roles of CAPG in ovarian cancer. CAPG expression and clinical information were investigated in the data collected from TCGA, Oncomine, GEPIA, UALCAN, and Kaplan-Meier plotter. CAPG coexpression networks were evaluated by LinkedOmics, GeneMANIA, and NetworkAnalyst. The correlation of CAPG with immune infiltrates was analyzed via TIMER, ImmuCellAI, and GEPIA. Our result showed that patients with high tumoral CAPG expression had significantly shorter 5-year overall survival. Functional enrichment analysis indicated that CAPG-related phenotypes were largely involved in inflammatory response, chemokine and cytokine signaling, cell adhesion, and Toll-like receptor signaling pathways. CAPG expression was positively correlated with infiltrating levels of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and exhausted T cells (Texs) while being negatively correlated with infiltrating levels of natural killer T cells (NKTs) and neutrophils in ovarian cancer. Moreover, the expression of FOXP3, CD25, CD127, CCR8, and TGFß in respect to Tregs; CCL2 and CD68 in respect to TAM; CD163, VSIG4, and MS4A4A in respect to M2 macrophages; CD33 and CD11b in respect to myeloid-derived suppressor cells (MDSCs); and PD1, CTLA4, LAG3, TIM3, GZMB, 2B4, and TIGIT in respect to Texs was significantly correlated with CAPG expression in ovarian cancer. These findings suggest that CAPG may contribute to the immunosuppressive tumor microenvironment in ovarian cancer, leading to an exhausted T cell phenotype and tumor progression. Therefore, CAPG can be used as a potential biomarker for determining prognosis and immunotherapy effectiveness in ovarian cancer.

OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway.

Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1. Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We first validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we confirmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing.

Background: Cervical cancer is one of the leading causes of cancer-related deaths worldwide. The unspliced human papillomavirus (HPV) E6 plays an important role in tumor progression and immune regulation. Improved immunotherapy implementation might benefit from a better knowledge of HPV E6 splicing-related immune gene expressions and immunocyte infiltration in cervical cancer. This study aimed to identify the potential therapeutic and prognostic roles of unspliced/spliced E6 ratio (E6 ratio) in cervical cancer. Methods: Data from the TCGA were used to analyze the E6 condition and clinical information. Nomogram and K-M analysis were used to analyze assess the prognostic significance, IOBR was used to investigate immunological infiltrates. Functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A core module was taken from the competitive endogenous RNA (ceRNA) network and used to build a lncRNA-miRNA-mRNA network. QT-qPCR was used to detect the expression of genes. CCK-8, colony formation, wound healing and migration assays were used to detect cell functions. Results: Our study found that HPV E6 ratio had significantly correlation with overall survival. In cervical cancer, a high E6 ratio was adversely linked with infiltrating levels of aDC, M1 macrophages, monocytes, NKT, and Tgd. High E6 ratio phenotypes were shown to be implicated in immune response regulation, cell adhesion, and Wnt signaling pathways, according to functional enrichment analysis. Subsequently, we constructed an immune-related ceRNA network based on E6 splicing in cervical cancer, including three lncRNA (LINC00943, LIFR-AS1, DANT2, and RASSF8-AS1), four miRNA (miR-205-5p, miR-181d-5p, miR-222-3p, and miR-221-3p), and seven mRNA (FGFR1, PRLR, CXCL2, ISG20, ISG15, SDC1, and NR2F2). Among them, CXCL2, SDC1, and miR-221-3p were associated with survival and immune cell infiltration. Conclusions: These data imply that a high E6 ratio in cervical cancer contributes to the immune-related ceRNA network, resulting in a low amount of infiltrating effector immune cells and tumor growth. As a result, the E6 ratio might be employed as a biomarker in cervical cancer to determine prognosis and treatment success.

Comprehensive Analysis of Prognostic Alternative Splicing Signatures in Endometrial Cancer.

BACKGROUND: Alternative splicing (AS) is one of the critical post-transcriptional regulatory mechanisms of various cancers and also plays a crucial role in the development of cancers, including endometrial cancer (EC). METHODS: The splicing data and gene expression profiles of EC were obtained from The Cancer Genome Atlas. The corresponding clinical data were extracted from TCGA-CDR. With univariate Cox regression analysis, least absolute shrinkage and selection operator model, and multivariate Cox regression analysis, the survival-related AS events were selected. Functional enrichment analysis was also performed to investigate the functions of these AS events. Splicing factors and AS regulation network were constructed to understand the correlation among these AS events. RESULT: A total of 1826 AS events were identified as survival-related events. Functional enrichment analysis showed that these AS events were associated with several immune system-related processes. Then, the prognostic signatures were developed based on these survival-related events and acted as an independent prognostic factor for EC. Splicing factors and AS regulation network were also constructed to understand the regulatory mechanisms of AS events in EC. CONCLUSION: This study systematically analyzed the role of AS events in EC and developed the prognostic model for EC.

Identification of prognostic immune-related genes in the tumor microenvironment of endometrial cancer.

Endometrial cancer (EC) is one of the most common gynecologic malignancies. To identify potential prognostic biomarkers for EC, we analyzed the relationship between the EC tumor microenvironment and gene expression profiles. Using the ESTIMATE R tool, we found that immune and stromal scores correlated with clinical data and the prognosis of EC patients. Based on the immune and stromal scores, 387 intersection differentially expressed genes were identified. Eight immune-related genes were then identified using two machine learning algorithms. Functional enrichment analysis revealed that these genes were mainly associated with T cell activation and response. Kaplan-Meier survival analysis showed that expression of TMEM150B, CACNA2D2, TRPM5, NOL4, CTSW, and SIGLEC1 significantly correlated with overall survival times of EC patients. In addition, using the TIMER algorithm, we found that expression of TMEM150B, SIGLEC1, and CTSW correlated positively with the tumor infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, and dendritic cells. These findings indicate that the composition of the tumor microenvironment affects the clinical outcomes of EC patients, and suggests that it may provide a basis for development of novel prognostic biomarkers and immunotherapies for EC patients.

Overexpression of YES1 is associated with favorable prognosis and increased platinum-sensitivity in patients with epithelial ovarian cancer.

AIMS: The prognostic application of YES1 in epithelial ovarian cancer (EOC) is currently unclear. We aimed to investigate the expression of YES1 and its correlation with survival outcome in patients with EOC. METHODS: A retrospective study of patients diagnosed with EOC at the Cancer Center, Sun Yat-Sen University, Guangzhou, China between 2002 and 2013 was conducted. The immunohistochemical expression of YES1 was assessed using tissue microarray. Survival rates were analyzed by the Kaplan-Meier method and were compared between groups using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model. RESULTS: A total of 132 patients with EOC were enrolled. Patients in the YES1-high group exhibited significantly better OS and PFS, compared with those in the YES1-low group (P=0.02 and P=0.03, respectively). Further univariate and multivariate regression analyses indicated YES1 as an independent prognostic factor for the OS of patients with EOC. Notably, within the high YES1 expression group, 40 cases (74.1%) were of the platinum-sensitive group while 14 (25.9%) overlapped were of the platinum-resistant group. Conversely, in the low YES1 expression group, 11 cases (47.8%) were platinum-sensitive, and 12 (52.2%) platinum-resistant. Overall, patients within the high YES1 expression group were deemed significantly more sensitive to platinum-based chemotherapy than the low YES1 expression group (P=0.03), and YES1 levels were consistently and significantly higher in the platinum-sensitive group. CONCLUSIONS: High YES1 cytoplasmic expression in EOC patient tissue is significantly correlated with favorable prognosis. Patients with high YES1 expression tend to be sensitive to platinum-based chemotherapy.

Combined prognostic value of the cancer stem cell markers CD47 and CD133 in esophageal squamous cell carcinoma.

BACKGROUND: Treatments based on the inhibition of pivotal signals of cancer stem cells (CSCs) are on a promising track. Recent studies have shown that targeting CSCs with broader immune-based therapeutic methods, for example, the anti-CD47 treatment, may serve as a more potent strategy for eliminating these intractable cells. We aimed to explore the prognostic effects of CD47/CD133 and the potential therapeutic significance of CD47 in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemistry was employed to identify the characteristics of CD47 and CD133 in 26 pairs of tumor tissues and adjacent non-tumor tissues and 136 ESCC tissues. Kaplan-Meier analysis and Cox proportional hazards models were built for estimating the prognostic values of CD47 and CD133 expression and their combined stemness index. Sphere formation assays were undertaken to explore the effects of CD47 inhibition on primary human ESCC CSCs. RESULTS: Results conclude that CD47 and CD133 expression is increased in tumor tissues as compared to adjacent non-tumor tissues. A positive correlation between CD47/CD133 expression and differentiation was found in 136 ESCC patients. Survival analysis indicated that patients with high CD47 or CD133 expression exhibited poor overall survival and progression-free survival (PFS). The combination of high CD47 and CD133 expression was a reliable independent prognostic factor for both OS (HR = 1.940, 95% CI = 1.399-2.690, P < 0.0001) and progression-free survival (HR = 1.883, 95% CI = 1.384-2.562, P < 0.0001). Notably, CD47+ CD133+ ESCC cells were observed to possess the characteristics of CSCs, and anti-CD47 treatment veritably eliminated the CSCs pool. CONCLUSIONS: The stemness index determined by the expression of CD47 and CD133 is a promising prognostic predictor, and CD47 is a potential therapeutic target for CSCs in ESCC patients.

Retrospective analysis of the efficacy of adjuvant CIK cell therapy in epithelial ovarian cancer patients who received postoperative chemotherapy.

Cytokine-induced killer (CIK) cells are demonstrated to possess potent cytolytic effect against ovarian cancer cells in vitro and in vivo. However, the clinical efficacy of maintenance therapy of CIK cells in patients with epithelial ovarian cancer (EOC) after first-line treatment remains unclear. This retrospective study included 646 cases of postoperative EOC patients, 72 of which received chemotherapy and sequential immunotherapy (CIT group), and 574 of which received only chemotherapy (Control group). Patients in the CIT group received at least four cycles of CIK cell (range 8.0 × 109 - 1.3 × 1010 cells) transfusion, with the interval of each cycle being 2 weeks. Survival analysis showed a significantly higher overall survival (OS) rate in the CIT group compared with the control group, as well as a favorable progression-free survival (PFS). Univariate and multivariate analyses indicated that adjuvant CIT was an independent prognostic factor for the OS of patients with EOC. Furthermore, subgroup analyses showed that adjuvant CIT significantly improved the OS of patients older than 45 years, with CA125 ≤ 1000, or with moderate or poorly differentiated tumors, and prolonged the PFS of patients with residual disease > 1 cm. Additionally, Kaplan-Meier analyses revealed that a higher fraction of CD3+CD8+/CD3+CD56+ phenotypes or lower percentage of CD3+CD4+/CD3-CD56+ phenotypes in the infused CIK cells significantly associated with better survival of patients with EOC. Furthermore, across all processes of CIK cell immunotherapy in the CIT group, 12.5% (9/72) of patients developed self-limiting light fevers and shivering at grade 1 or 2. No immunotherapy-related serious reactions were recorded. These data indicate that adjuvant CIT with CIK cells is an effective therapeutic approach to prolonging the survival of EOC patients.