Xiaoxu Zhao

Gold Nanoparticle-Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy.

Tumour vasculature is generally disordered because of the production of excessive angiogenic factors by tumour cells, which results in tumour progression and reduces the effectiveness of radiotherapy or chemotherapy. Transient anti-angiogenic therapies that regulate tumour vascular morphology and function and improve the efficiency of antitumour therapy are under investigation. Recombinant human endostatin (Endostar/rhES) is a vascular angiogenesis–disrupting agent that has been used to treat non-small cell lung cancer (NSCLC) in the clinical setting. In this study, we used gold nanoparticles (AuNPs) as a drug-delivery system (DDS) for targeted tumour delivery of rhES for short therapy, which resulted in transient tumour vascular normalization, reduced permeability and hypoxia, strengthened blood vessel integrity, and increased blood-flow perfusion. Moreover, combination therapy with 5-FU over this timeframe was substantially more effective than 5-FU monotherapy. In conclusion, our research demonstrates the potential use of AuNPs as a drug-delivery platform for transporting rhES into a tumour to induce transient tumour vascular normalization and enhance the antitumour efficacy of cytotoxic drugs.

Inhibition effects of gold nanoparticles on proliferation and migration in hepatic carcinoma-conditioned HUVECs

Tumor angiogenesis is a complicated process based upon a sequence of interactions between tumor and vessel endothelial cells. Tumor conditioned medium has been widely used to stimulate endothelial cells in vitro angiogenesis. This work was aimed to investigate the effects of gold nanoparticles (GNPs) on angiogenesis in hepatic carcinoma-conditioned endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured with conditioned medium (CM) from the human hepatocarcinoma cell line HepG2 (HepG2-CM), and then treated with different concentrations of GNPs. The effects of GNPs on the viability, migration and active VEGF level of HUVECs were investigated by MTT assay, wound healing assay and transwell chamber assay, and ELISA assay, respectively. The data showed that GNPs significantly inhibited HUVECs proliferation and migration induced by HepG2-CM, and also reduced the levels of active VEGF in the co-culture system. Then, the alterations in morphology and ultrastructure of HUVECs detected by atomic force microscopy (AFM) showed that there appeared obvious pseudopodia, larger membrane particle sizes and much rougher surface in HUVECs after HepG2-CM treatment, which were all reversed after GNPs treatment. Changes in cytoskeleton of HUVECs determined by immunocytochemistry demonstrated that GNPs treatment remarkably inhibited the activation effect of HepG2-CM on HUVECs, which was associated with the disruption of actin filaments induced by GNPs. This study indicates that GNPs can significantly inhibit HepG2-CM activated endothelial cell proliferation and migration through down-regulation of VEGF activity and disruption of cell morphology, revealing the potential applications of GNPs as antiangiogenic agent for the treatment of hepatic carcinoma.

Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2–mediated angiogenesis

Several studies have revealed the potential of normalizing tumor vessels in anti-angiogenic treatment. Recombinant human endostatin is an anti-angiogenic agent which has been applied in clinical tumor treatment. Our previous research indicated that gold nanoparticles could be a nanoparticle carrier for recombinant human endostatin delivery. The recombinant human endostatin–gold nanoparticle conjugates normalized vessels, which improved chemotherapy. However, the mechanism of recombinant human endostatin–gold nanoparticle–induced vascular normalization has not been explored. Anterior gradient 2 has been reported to be over-expressed in many malignant tumors and involved in tumor angiogenesis. To date, the precise efficacy of recombinant human endostatin–gold nanoparticles on anterior gradient 2–mediated angiogenesis or anterior gradient 2–related signaling cohort remained unknown. In this study, we aimed to explore whether recombinant human endostatin–gold nanoparticles could normalize vessels in metastatic colorectal cancer xenografts, and we further elucidated whether recombinant human endostatin–gold nanoparticles could interrupt anterior gradient 2–induced angiogenesis. In vivo, it was indicated that recombinant human endostatin–gold nanoparticles increased pericyte expression while inhibit vascular endothelial growth factor receptor 2 and anterior gradient 2 expression in metastatic colorectal cancer xenografts. In vitro, we uncovered that recombinant human endostatin–gold nanoparticles reduced cell migration and tube formation induced by anterior gradient 2 in human umbilical vein endothelial cells. Treatment with recombinant human endostatin–gold nanoparticles attenuated anterior gradient 2–mediated activation of MMP2, cMyc, VE-cadherin, phosphorylation of p38, and extracellular signal–regulated protein kinases 1 and 2 (ERK1/2) in human umbilical vein endothelial cells. Our findings demonstrated recombinant human endostatin–gold nanoparticles might normalize vessels by interfering anterior gradient 2–mediated angiogenesis in metastatic colorectal cancer.

Long-term oncological outcomes in robotic gastrectomy versus laparoscopic gastrectomy for gastric cancer: a meta-analysis

BackgroundRobotic gastrectomy (RG) has been a new technical alternative for gastric cancer. However, the long-term oncological outcomes of RG still should be further evaluated. In this meta-analysis, the long-term oncological outcomes of RG and laparoscopic gastrectomy (LG) are compared.MethodsComprehensive searches from various databases are compared in February 2017 to identify that the oncological outcomes of RG and LG are evaluated in gastric cancer patients. The pooled oncological outcomes of the overall survival (OS), disease-free survival (DFS), and the recurrence rate were performed by adopting the meta-analysis to calculate the hazard ratio (HR) or the odds ratio with 95% confidence intervals (CIs).ResultsFive studies that concern retrospective design and prospective data collection and involve 1614 patients were included. All the five studies evaluated OS. Two studies evaluated DFS, while four studies reported the recurrence rate or recurrence cases in RG and LG groups with the long-term follow-up. The pooled analysis showed no significant difference in OS and DFS between RG and LG, without significant between-study heterogeneity. Besides, the recurrence rate between RG and LG had no significant difference without heterogeneity.ConclusionsRG could provide comparable long-term oncological outcomes as well as LG for the treatment of gastric cancer. OS, DFS, and the recurrence rate by the long-time follow-up of RG were comparable with LG. Generally speaking, more randomized clinical trials and a larger patient cohort with longer follow-up are still essential to further demonstrate the value of the robotic surgery for gastric cancer.

Anterior gradient 2 as a supervisory marker for tumor vessel normalization induced by anti‑angiogenic treatment

Anti-angiogenic therapy provides transient tumor vascular normalization, which results in a window of opportunity for improvement of radio- or chemotherapy. Biomarkers indicating this window are required for rationalizing anti-angiogenesis. Anterior gradient 2 (AGR2), the majority of which is secreted from tumor cells, is an easily detected plasma protein. In the present study, it was demonstrated that AGR2 could be applied as a biomarker for the supervision of vascular normalization during anti-angiogenic treatment with gold nanoparticles (AuNPs). Nude mice inoculated with SW620 human colorectal cancer cells were treated with AuNPs. Vessel density, pericyte coverage, vessel permeability, tumor hypoxia, tumor growth and AGR2 secretion were detected following treatment with AuNPs at days 0, 4, 6, 9 and 14. Tumor volume and vessel density were reduced, whereas pericyte coverage was increased, and hypoxia and vessel permeability were improved between days 6–9; however, these improvements decreased by day 14, revealing a time frame for tumor vascular normalization, namely days 4–9, during treatment with AuNPs in mice. AGR2 levels in tumor tissues and plasma were significantly low at day 9, along with vascular normalization; therefore, AGR2 can be used as a potential marker for monitoring tumor vascular normalization during anti-angiogenic treatment.

Nicotinamide phosphoribosyl transferase regulates cell growth via the Sirt1/P53 signaling pathway and is a prognosis marker in colorectal cancer: PAN et al.

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus‐mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase‐3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.

Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer

RAF kinase is crucially involved in cell proliferation and survival in colorectal cancer (CRC). Patients with metastatic CRC (mCRC) harboring BRAF mutations (BRAFms) not only experience a poor prognosis but also benefit less from therapeutics targeting ERK signaling. With advances in RAF inhibitors and second-generation inhibitors including encorafenib and vemurafenib, which have been approved for treating BRAF-V600E malignancies, the combinatorial therapeutic strategies of RAF inhibitors elicit remarkable responses in patients with BRAF-V600E mCRC. However, the therapeutic efficacy is restricted by resistance, which might be due to RAF dimerization and reactivation of the MAPK pathway. In addition, the next-generation RAF inhibitors, which are characterized by varying structural and biochemical properties, have achieved preclinical and clinical advances. Herein, we summarize the existing mechanism of RAF kinases in CRC, including MAPK feedback reactivation of resistance to RAF inhibitors. We additionally summarize the development of three generations of RAF inhibitors and different therapeutic strategies including the combination of EGFR, BRAF, and PI3K inhibitors for BRAFm CRC treatment.