Experimental Study of Hepatic Artery Infusion of Vascular Endothelial Growth Factor Receptor (VEGFR)-2As2O3 Nanospheres for Targeted Therapy of Implanted Hep G2 Liver Cancer in Rats

This study assesses the effect of VEGFR-2/As2O3 invisible nanospheres on treating liver cancer. The following groups were set: Group I: blank control group (hepatic artery perfusion 0.9% saline 0.5 ml), group II: VEGFR-2/As2O3 nanospheres injection via tail vein, group III: hepatic artery perfusion of VEGFR-2/As2O3 nanospheres. The effect of hepatic artery infusion of VEGFR-2/As2O3 nanospheres on cell proliferation, apoptosis and colony forming ability was evaluated by MTT method, flow cytometry and colony formation experiment. Tumor xenotransplantation was established to observe the effect of hepatic artery infusion of VEGFR-2/As2O3 nanospheres on liver cancer. The in vivo and in vitro experiments both confirmed that hepatic artery perfusion of VEGFR-2/As2O3 nanospheres can inhibit the proliferation of liver cancer cells, promote cell apoptosis and inhibit cell migration, thereby enhancing the therapeutic effect. The hepatic artery perfusion of VEGFR-2As2O3 nanospheres may be used as a targeted research and development direction for the treatment of liver cancer, providing a new and efficient targeted drug for the interventionaltreatment of liver cancer.

Up-Regulation of miR-1925 by Bone Marrow Mesenchymal Stem Cell (BMSC) Inhibits the Growth of Liver Cancer by Promoting the Anti-Tumor Activity of Natural Killer (NK) Cells

Hepatocellular carcinoma (HCC) seriously threatens human health and life quality. Natural killer (NK) cells play important roles in liver immune function. Bone marrow mesenchymal stem cell (BMSC) exosomes (Exo) participate in tissue damage. This study explored BMSC-Exo’s effect on NK cells’ anti-tumor activity. NK cells were isolated from the livers of mice with liver cancer. NK cells with or without BMSC-Exo treatment were co-cultured with liver cancer cells to assess cell proliferation. Administration of BMSC-Exo into mice with liver cancer significantly suppressed liver cancer cell growth. In addition, BMSC-Exo treatment significantly improved NK cells’ anti-tumor effect whic was related to BMSC-Exo-induced up-regulation of miR-1925. Implantation of BMSC-Exo into mice with liver cancer at different time periods can significantly suppress liver cancer cell growth. At the same time, BMSC-Exo implantation inhibited the expression of cell proliferation marker protein(Ki67). In vitro study found that BMSC-Exo treatment significantly increased miR-1925 level and the toxicity of NK cells to HCC cells. In addition, miR-1925 overexpression in NK cells significantly increased NK cells’ anti-tumor activity. In conclusion, this study proved that up-regulation of miR-1925 by BMSC can inhibit the growth of liver cancer by promoting the anti-tumor activity of NK cells.

MiRNA-136-5p Sensitizes Liver Cancer Cells to Docetaxel by Targeting P53 and Enhances Cell Migration

We aimed to explore whether microRNA (miRNA)-136-5p modulates P53 expression, and affects the efficacy of docetaxel treatment for liver cancer. miRNA array screened the differentially expressed miRNAs in biopsy tissues of liver cancer patients, and the expression of miR-136-5p and P53 in tissues and cells by RT-PCR. Following docetaxel treatment, through increased- and decreased-function method, we detected the impact of the miRNA on cell progression, as well as the sensitivity of docetaxel through MTT assay and colony formation experiment. The correlation between miR-136-5p and P53 was evaluated. The expression of miR-136-5p in liver cancer cells is up-regulated, which is consistent with the results of bioinformatics analysis. Further, miR-136-5p overexpression promoted cell proliferation and migration, and sensitized liver cancer cells to docetaxel. Interestingly, P53 was indicated to bind to miR-136-5p, and P53 participated in the up-regulation of MMP10 induced by miR-136-5p. miR-136-5p enhances the sensitivity to docetaxel in liver cancer and thus could be a biomarker for the treatment against liver cancer.

Azaindole inhibits liver cancer cell proliferation in vitro and in vivo by targeting the expression of kinesin family member C1

Purpose: To investigate the effect of azaindole on proliferation of liver cancer cells, as well as the underlying mechanism. Methods: Colony forming and 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assays were used to determine the effect of azaindole on cell proliferation. A tumor model was established through subcutaneous administration of HEPG2 cells to rats. Thereafter, in vivo tumor development was measured using Vernier caliper. Results: The proliferation potential of HEPG2 and SNU-398 cells was markedly and dose-dependently suppressed by treatment with azaindole at doses of 2, 4, 8, 16 and 20 μM (p < 0.05). The expression levels of Ki67 and PCNA levels were significantly down-regulated in HEPG2 and SNU-398 cells on treatment with 20 μM azaindole. Moreover, azaindole significantly suppressed mRNA and protein expressions of KIFC1 in HEPG2 and SNU-398 cells (p < 0.05). Tumor volume in azaindole-treated rats on day 21 was greatly reduced, while KIFC1 expression in azaindole-treated rat tumor tissue was significantly down-regulated, when compared to the model group (p < 0.05). Conclusion: Azaindole targets proliferation of liver cancer cells in vitro and inhibits tumor growth in vivo through a mechanism involving down-regulation of KIFCI expression. Thus, azaindole is a potential therapeutic candidate for liver cancer.

FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification

PurposeThis work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode.Methods and MaterialsAn in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s).ResultsAll plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans.ConclusionThis is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.