The effects of anti-PD-L1 monoclonal antibody on the expression of angiogenesis and invasion-related genes.

Background/aim: The role of PD-L1 in regulating the immunosuppressive tumor microenvironment via its binding on PD-1 receptors is extensively studied. The PD-1/PD-L1 axis is a significant way of cancer immune escape, and PD-L1 expression on tumor cells is suggested as a predictive marker for anti-PD-1/PD-L1 monoclonal antibodies (MoAbs). However, the tumor-intrinsic role of PD-L1 is not known well. Therefore, we aimed to investigate the effects of anti-PD-L1 antibodies on the expression of angiogenesis and metastasis-related genes in tumor cells. Materials and methods: The experiments were done with prostate cancer and melanoma cells with low PD-L1 expression (<5%) and prostate and breast cancer cells with high PD-L1 expression (>50%). The gene and protein expressions of VEGFA, E-cadherin, TGFß1, EGFR, and bFGF in tumor cells were assayed at the 3 different doses of the anti-PD-L1 antibody. Results: We found that VEGFA, E-cadherin and TGFß1 expressions increased in PD-L1 high cells but decreased in PD-L1 low cells after anti-PD-L1 treatment. EGFR expression levels were variable in PD-L1 high cells, while decreased in PD-L1 low cells upon treatment. Also, the anti-PD-L1 antibody was found to increase bFGF expression in the prostate cancer cell line with high PD-L1 expression. Conclusion: Our results suggest that the binding of PD-L1 on tumor cells by an anti-PD-L1 monoclonal antibody may affect tumor-intrinsic mechanisms. The activation of angiogenesis and metastasis-related pathways by anti-PD-L1 treatment in PD-L1 high tumors might be a tumor-promoting mechanism. The decrease of VEGFA, TGFß1 and EGFR upon anti-PD-L1 treatment in PD-L1 low tumor cells provides a rationale for the use of those antibodies in PD-L1 low tumors.

Recent Advances in Cancer Stem Cell Targeted Therapy.

The cancer stem cells (CSCs) are a subpopulation of cancer cells with unique properties of self-renewal and differentiation potential. Recent evidence suggests that these cells might be responsible for tumor relapse and treatment resistance. Conventional cancer treatment modalities like chemotherapy and radiotherapy usually fail in eradicating CSCs in a tumor mass. Preclinical studies aiming at targeting CSCs have yielded great promise to increase the cancer cure rate. Likewise, targeting of conventional chemotherapeutic drugs to the CSCs and new small molecule inhibitors of stem-cell signaling pathways in humans carry the potential of improving the cancer management. Dendritic cell (DC)-based vaccines seem to be safe and efficient tools in targeting CSCs. The combination of DC vaccines with immune-checkpoint inhibitors is also promising. The viral vectors, particularly the oncolytic viruses, targeting CSCs have emerged as potential curative agents in cancer treatment. Here, we review the recent advances in targeting CSCs via stem cell markers, signaling pathways, immune system, cancer vaccines, and viral treatments.

The effects of melatonin and curcumin on the expression of SIRT2, Bcl-2 and Bax in the hippocampus of adult rats.

OBJECTIVE: Though the mechanisms are not clearly understood, melatonin and curcumin have been reported to have neuroprotective effects. However, the mechanisms of neuroprotective effects of melatonin and curcumin in the brain are not clearly understood. In the current study, we investigated the effects of melatonin and curcumin treatments on oxidative stress parameters, the expression of SIRT2, Bcl-2 and Bax in the hippocampus. METHODS: A total of thirty adult (13 months-old) male Wistar rats were divided into five groups: Control (1% ethanol:PBS), s.c. for 30 days), dimethyl sulfoxide (10%, s.c. for 30 days), Melatonin (10 mg/kg/day, s.c. for 30 days), Curcumin (30 mg/kg/day, i.p. for 30 days) and Salermide (100 µM, i.p. for 30 days). The levels of malondialdehyde (MDA) glutathione (GSH) were measured as oxidative stress parameters in the hippocampus. The expression levels of SIRT2, Bcl-2 and Bax proteins were tested by western blotting and the SIRT2 protein levels of the hippocampal region was measured by a sandwich ELISA method. RESULTS: Melatonin and curcumin significantly decreased MDA and SIRT2 expression in the hippocampus (p < 0.05). Accordingly, a significant increase in the GSH levels of curcumin-treated group and melatonin-treated group was observed. Melatonin, but not curcumin, significantly increased the Bcl-2 expression of the hippocampal region. There was a significant correlation between SIRT2 and MDA levels (p < 0.05). DISCUSSION: In conclusion, our results suggest that melatonin may increase cell survival in the hippocampus via decreasing oxidative stress and SIRT2 expression and increasing Bcl-2 expression.