Multimodal management of foregut neuroendocrine neoplasms.

The foregut, which includes the esophagus, stomach and duodenum, represents one of the most common sites for neuroendocrine neoplasms. These are highly heterogenous with different risk of progression depending on location, cell-type of origin, size, grade and other factors. Various endoscopic and imaging modalities exist to inform therapeutic decision-making, which may be in the form of surgical or endoscopic resection and medical therapy depending on the extent of the disease after diagnostic evaluation. This narrative review aims to explore the literature on the multimodal management of such foregut neuroendocrine neoplasms.

BRAFV600E mutation promoted the growth and chemoresistance of colorectal cancer.

BRAF mutation occurs frequently in colorectal cancer (CRC), which is associated with poor prognosis. Numerous clinical studies have indicated the undesirable effect of BRAF mutation in CRC patients; however, in vitro studies on the role and functional mechanism of BRAF mutation in CRC are limited. Here, we analyzed the association between BRAF mutation and the clinical features of CRC by using data deposited in the TCGA database. We found that BRAF mutation was closely related to the age and the pathological stage of CRC patients. Additionally, BRAF mutation also indicated poor overall survival in stage II CRC patients. Furthermore, we experimentally explored the function of BRAF mutation by generating a series of HCT116 stable cell lines expressing mutant BRAFV600E, wildtype BRAFWT, and vector control (NC). We found that BRAFV600E mutation promoted not only the invasion of HCT116 cells through inducing epithelial-mesenchymal transition (EMT), but also cell proliferation as well as the chemoresistance to 5-Fluorouracil (5-FU) and oxaliplatin. Moreover, we confirmed our in vitro findings in mouse xenograft model, in which tumors derived from BRAFV600E expressing HCT116 cells showed significantly increased growth compared with that from HCT116-BRAFWT and HCT116-NC cells. Consistently, HCT116-BRAFV600E tumors also showed significantly increased resistance to 5-FU compared with HCT116-BRAFWT and HCT116-NC tumors. Taken together, our study revealed that BRAF mutation not only promoted the progression of CRC via enhancing EMT but also enhanced chemoresistance.

Cancer-testis non-coding RNA LEF1-AS1 regulates the nuclear translocation of PDCD5 and suppresses its interaction with p53 signaling: a novel target for immunotherapy in esophageal squamous cell carcinoma.

Despite the improvement of current classical treatment, the prognosis of esophageal squamous cell carcinoma (ESCC) remains poor. Immunotherapy, as a new treatment method, has revolutionized the therapy of various cancer types and created more attractive for ESCC. Cancer-testis genes (CTGs), because of its characteristic expression and immunomodulation property, are considered as the ideal targets for tumor immunotherapy. However, the ESCC-specific CTGs, especially long non-coding RNA (lncRNA), has not been elucidated. In the present study, a systematic strategy was adopted to screen ESCC-specific cancer-testis lncRNA (CT-lncRNA). Collectively, 447 genes were recognized as ESCC-specific CT-lncRNAs, in particularly LEF1-AS1 showed the most aberrantly expression and clinically associated with poor outcome. Functional assays revealed that H3K27 acetylation in LEF1-AS1 promoter might give rise to the activation of LEF1-AS1 during ESCC tumorigenesis. The activated LEF1-AS1 was predominantly localized in the cytoplasm implicated in regulation of apoptosis and proliferation capacities of ESCC cells in vitro and in vivo. Further mechanistic studies unveiled that LEF1-AS1 participated in ESCC by interacting with RNA binding protein PDCD5 through weakened its nuclear translocation binding to TP53, leading to p53 degradation and disruption the transcription of downstream genes. Taken together, our findings suggest that LEF1-AS1 acts as a CT-lncRNA and might be an ideal immunotherapeutic target for clinical intervention for ESCC.

Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges.

The occurrence and development of cancer are closely related to the immune escape of tumor cells and immune tolerance. Unlike previous surgical, chemotherapy, radiotherapy and targeted therapy, tumor immunotherapy is a therapeutic strategy that uses various means to stimulate and enhance the immune function of the body, and ultimately achieves the goal of controlling tumor cells.With the in-depth understanding of tumor immune escape mechanism and tumor microenvironment, and the in-depth study of tumor immunotherapy, immune checkpoint inhibitors represented by Programmed Death 1/Programmed cell Death-Ligand 1(PD-1/PD-L1) inhibitors are becoming increasingly significant in cancer medication treatment. employ a variety of ways to avoid detection by the immune system, a single strategy is not more effective in overcoming tumor immune evasion and metastasis. Combining different immune agents or other drugs can effectively address situations where immunotherapy is not efficacious, thereby increasing the chances of success and alternative access to alternative immunotherapy. Immune combination therapies for cancer have become a hot topic in cancer treatment today. In this paper, several combination therapeutic modalities of PD1/PD-L1 inhibitors are systematically reviewed. Finally, an analysis and outlook are provided in the context of the recent advances in combination therapy with PD1/PD-L1 inhibitors and the pressing issues in this field.

Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR-146b-5p.

Cancer cachexia is a complex syndrome that is associated with thermogenic gene regulation. Currently, although some studies have reported the link between exosomes and cancer cachexia in a few types of cancer, the underlying mechanisms remain poorly understood. In this study, we tried to identify whether exosomes derived from colorectal cancer could affect lipolysis in vitro and in vivo. Here, we collected the tissue samples from 48 patients with colorectal cancer (47.91% females and mean age 55 ± 8.20) and 48 healthy people at the First Affiliated Hospital of Nanjing Medical University to detect the miR-146-5p expression. Here, we found that cancer cells released exosomes induced white adipose tissues (WATs) browning and accelerated lipolysis. We also demonstrated that miR-146b-5p was enriched in cancer-related exosomes. Overexpression miR-146b-5p resulted in increased WAT browning, decreased oxygen consumption, and fat mass loss (14.57%). The further study identified that miR-146b-5p could directly repress the downstream gene homeodomain-containing gene C10 (HOXC10), thereby regulating lipolysis. Therefore, our results indicated that cancer cells derived from exosomal miR-146b-5p played an essential role in WAT browning. Inhibition of cancer-related exosomes might be necessary for improving the cachexia condition.

miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating ß-catenin pathway.

Drug resistance remains the unresolved obstacle for gastric cancer (GC) treatment. Recently more and more studies have shown that microRNAs are involved in cancer resistance and could apply to drug resistance therapy in tumors. The relationship between miR-149 and 5-fluorouracil (5-FU) resistance in GC remains unclear. Here we detected miR-149 expression in 5-FU resistance tumor tissues and cell lines, and found that miR-149 expression is upregulated in AGS/5-FU cells compared with AGS cells. Further experiments indicated that overexpression of miR-149 can alleviate 5-FU-induced apoptosis and proliferation inhibition by targeting TREM2. It was also confirmed that TREM2 regulated 5-FU resistance through ß-catenin pathway. Generally speaking, our results indicated that miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating ß-catenin pathway.

Long-term exercise-secreted extracellular vesicles promote browning of white adipocytes by suppressing miR-191a-5p.

AIMS: The purpose of the study is to explore the mechanism of transdifferentiation from white adipose tissue (WAT) to Brown adipose tissue (BAT). MATERIALS AND METHOD: In this study, we established a model of mouse obesity induced by a high-fat diet (HFD) before 30 days of forced exercise or sedentary mice. Then, we isolated extracellular vesicles (EVs) from plasma and identified them by transmission electron microscope, dynamic light scattering and western blot analysis. Body temperature and body weight were utilized for assessment of thermogenesis in vivo. Oil red O staining was used to measure triglyceride in vitro. Luciferase reporter assay was applied for the relationship between miR-191a-5p and Prdm16. KEY FINDINGS: As a result, mice that exercised for a long period time exhibited higher caloric expenditure, better weight maintenance and more WAT browning, as well as better resistance to obesity associated with a high-fat diet, compared to mice that lacked exercise. MircoRNA-191-5p (miR-191-5p) was found to be lowly expressed in the EVs from mice with long-term exercise (Exe-EVs). Functional experiments revealed that Exe-EVs promoted WAT browning by the silencing of miR-191-5p. At the molecular level, siRNA-mediated PRDM16 partly inhibited uncoupling protein-1(UCP-1) expression by miR-191-5p inhibitor in white adipocytes. Here, we observed that the lowly expressed miR-191-5p in Exe-EVs promoted the browning of WAT by negatively targeting the PRDM16-3'-untranslated region (PRDM16-3'UTR), thereby enhancing heat production and reducing obesity. SIGNIFICANCE: MiR-191-5p may serve as a potential target for the identification and treatment of obesity.

Multiple roles of THY1 in gastric cancer based on data mining.

BACKGROUND: THY1 (CD90) is a heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored cell surface protein, which has been implicated in several cancers. But, the specific mechanism and function of the THY1 gene remains unclear in gastric cancer (GC). METHODS: To investigate the function of THY1 in GC and illustrate the potential mechanism, TCGA and FIREBROWSE were used to detect the THY1expression. GEPIA2 and Kaplan-Meier Plotter showed significant correlation among THY1 mRNA level, TNM stage and survival probability of GC patients. RESULTS: THY1 was up-regulated apparently in GC in contrast to normal tissues and linked to TNM stage. GC patients with higher THY1 expression displayed lower overall survival (OS), first progression (FP) and post-progression survival (PPS). In vitro experiments showed that knockdown of THY1 suppressed proliferation, migration while increased autophagy level in GC cells. Immune factors may interact with THY1mRNA in GC and THY1 was found significantly linked with Tregs. CONCLUSIONS: Our findings indicate that higher THY1 level is link to poor prognosis of GC patients. THY1may as well be used as a marker molecule for evaluating the tumor microenvironment status of GC patients and a target for immunotherapy.

The Superior Anticancer Effect of Self-Assembled Paclitaxel Nanofibers is Mediated Through Co-Operation Between Enhanced Apoptosis and Autophagic Cell Death.

Paclitaxel (Ptx) has been recommended as one of the main components of first-line chemotherapy for gastric cancer. However, the side effects of Ptx have greatly limited its clinical application because of its poor solubility and emerging resistance. In the current study, we designed novel self-assembled Ptx nanofibers with extremely high drug loading efficiency through conjugation of Ptx with succinic acid (sa), resulting in self-assembled nanofibers without the need for additional polymeric carriers. Cytotoxicity tests showed the superior effect of Ptx-sa against the gastric cancer cell lines SCG7901 and BGC823, but there was an obvious discrepancy between the number of apoptotic cells and dead cells, which indicates that other mechanisms may be involved in Ptx-sa-induced cell death. Mechanism studies, including apoptosis and autophagy detection, showed that Ptx-sa induced apoptosis and autophagy-induced cell death more efficiently than an equivalent dose of free Ptx. Most importantly, based on TEM and transfection with dual fluorescencelabeled LC3, more autophagosomes and increased autophagic flux were elicited by Ptx-sa in gastric cancer cells than an equivalent dose of free Ptx. Western blotting demonstrated that Ptx-sa induced the expression of LC3 II, a marker of autophagy, much more effectively than free Ptx. Moreover, an in vivo study demonstrated that Ptx-sa nanofibers significantly enhanced the anti-cancer effect of Ptx. Therefore, the self-assembled Ptx-sa nanofibers may exert cytotoxicity by inducing both apoptosis and autophagic cell death and thus might be a promising strategy to strengthen the therapeutic efficacy of Ptx in gastric cancer.

Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma.

Ursolic acid (UA) induces apoptosis in gastric cancer cells by inhibiting cyclooxygenase-2 (COX-2). Paclitaxel (PTX) is an important chemotherapy agent used to treat solid tumors. We evaluated the in vitro antitumor activity of UA in combination with PTX against gastric cancer cells and investigated the mechanisms underlying the combined effects. A cytotoxicity test and flow cytometry were utilized to study the effects of UA and PTX on proliferation and apoptosis, respectively. To further elucidate the mechanism, Western blot analysis was used to assess changes in the expression of a series of related proteins, including COX-2, proliferating cell nuclear antigen (PCNA), Bcl-2, and Bax. UA and PTX dose- and time-dependently inhibited BGC-823 and SGC-7901 gastric cancer cell proliferation. Combined delivery of UA and PTX synergistically reduced cell proliferation and induced apoptosis in these cells by lowering COX-2, PCNA, and Bcl-2 expression and by increasing Bax expression. These results indicate that the synergistic inhibition of proliferation and induction of apoptosis by UA and PTX may be induced by reducing COX-2 expression in gastric cancer cells.

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells.

The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.

Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells.

Gastrin, cholecystokinin2 receptor (CCK2R), and cyclooxygenase-2 (COX-2) have been implicated in the carcinogenesis and progression of gastric cancer. Our study demonstrated that antagonist or siRNA against CCK2R blocked amidated gastrin (G17)-induced activation of STAT3 and Akt in gastric cancer cell lines. G17-increased COX-2 expression and cell proliferation were effectively blocked by CCK2R antagonist and inhibitors of JAK2 and PI3K. In addition, knockdown of STAT3 expression significantly attenuated G17-induced PI3K/Akt activation, COX-2 expression, and cell proliferation. These results suggest that CCK2R-mediated COX-2 up-regulation via JAK2/STAT3/PI3K/Akt pathway is involved in the proliferative effect of G17 on human gastric cancer cells.