Optimization of BCG Therapy Targeting Neutrophil Extracellular Traps, Autophagy, and miRNAs in Bladder Cancer: Implications for Personalized Medicine

Abstract

Bladder cancer (BC) is the ninth most common cancer and the thirteenth most common cause of mortality worldwide. Bacillus Calmette Guerin (BCG) instillation is a common treatment option for BC. BCG therapy is associated with the less adversary effects, compared to chemotherapy, radiotherapy, and other conventional treatments. BCG could inhibit the progression and recurrence of BC by triggering apoptosis pathways, arrest cell cycle, autophagy, and neutrophil extracellular traps (NETs) formation. However, BCG therapy is not efficient for metastatic cancer. NETs and autophagy were induced by BCG and help to suppress the growth of tumor cells especially in the primary stages of BC. Activated neutrophils can stimulate autophagy pathway and release NETs in the presence of microbial pathogenesis, inflammatory agents, and tumor cells. Autophagy can also regulate NETs formation and induce production of reactive oxygen species (ROS) and NETs. Moreover, miRNAs are important regulator of gene expression. These small non-coding RNAs are also considered as an essential factor to control the levels of tumor development. However, the interaction between BCG and miRNAs has not been well-understood yet. Therefore, the present study discusses the roles of miRNAs in regulations of autophagy and NETs formation in BCG therapy in the treatment of BC. The roles of autophagy and NETs formation in BC treatment and efficiency of BCG are also discussed.

A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases

“…Inflammatory factors and microbial pathogenic factors activate neutrophils by stimulating the autophagy pathway and NET release. 216 Our team also confirmed that RA patients with joint fluid had significantly higher levels of neutrophil autophagy than peripheral blood neutrophils. 217 Previous studies have shown that autophagy-related light chain 3 (LC3) protein expression is upregulated in neutrophils isolated from RA synovial fluid when lysosomal pH in neutrophils is decreased or cells are exposed to chloroquine (CQ) and small interfering RNA (siRNA) Atg5 transfection.…”

RAC3 Inhibition Induces Autophagy to Impair Metastasis in Bladder Cancer Cells via the PI3K/AKT/mTOR Pathway

“…Autophagy is a tumor-suppressive mechanism that maintains genomic integrity and suppresses tumorigenesis ( 60 , 61 ), as occurs with RAC3 knockdown cells. Activation of PI3K/AKT/mTOR, an important pathway regulating autophagy, is prevalent in many cancers and may be responsible for reducing cytoprotective autophagy and deregulated proliferation ( 62 ). Studies have confirmed that targeting autophagy in combination with other treatment strategies is generally more effective than monotherapy ( 63 ).…”

The Cross-talk, Genetic Alteration, Molecular Functions, and Cluster Relevance of the Major Types of Regulated Cell Death in Bladder Cancer

“…In-depth exploration of these complex mechanisms, exploiting the chemical modulators currently available for blocking or triggering these cell death methods is essential to treat cancer, infectious diseases, and autoin ammatory by promoting the development of precise therapeutic targets 70 . Some RCD types have been found to correlate to multiple chemotherapeutic drugs in treating bladder cancer [78][79][80][81] . However, few mechanism studies were performed on RCD types in bladder cancer 82 .…”