Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

Abstract

Bladder cancer is a common malignant tumor of the urinary system. Despite recent advances in treatments such as local or systemic immunotherapy, chemotherapy, and radiotherapy, the high metastasis and recurrence rates, especially in muscle-invasive bladder cancer (MIBC), have led to the evaluation of more targeted and personalized approaches. A fundamental understanding of the tumorigenesis of bladder cancer along with the development of therapeutics to target processes and pathways implicated in bladder cancer has provided new avenues for the management of this disease. Accumulating evidence supports that the tumor microenvironment (TME) can be shaped by and reciprocally act on tumor cells, which reprograms and regulates tumor development, metastasis, and therapeutic responses. A hostile TME, caused by intrinsic tumor attributes (e.g., hypoxia, oxidative stress, and nutrient deprivation) or external stressors (e.g., chemotherapy and radiation), disrupts the normal synthesis and folding process of proteins in the endoplasmic reticulum (ER), culminating in a harmful situation called ER stress (ERS). ERS is a series of adaptive changes mediated by unfolded protein response (UPR), which is interwoven into a network that can ultimately mediate cell proliferation, apoptosis, and autophagy, thereby endowing tumor cells with more aggressive behaviors. Moreover, recent studies revealed that ERS could also impede the efficacy of anti-cancer treatment including immunotherapy by manipulating the TME. In this review, we discuss the relationship among bladder cancer, ERS, and TME; summarize the current research progress and challenges in overcoming therapeutic resistance; and explore the concept of targeting ERS to improve bladder cancer treatment outcomes.

Calreticulin promotes EMT in pancreatic cancer by enhancing endoplasmic reticulum stress-induced autophagy

“…CRT silencing inhibited ERS-induced cell mobility and chemoresistance via promoting autophagy in vitro ERS, as a series of adaptive changes mediated by UPR, takes part in cancer development via mediated tumor malignant behavior (proliferation, migration, apoptosis and survival) and autophagy [22,23]. In current study, transwell assays rst showed that TG signi cantly induced cell invasion and migration in Capan-2, Miapaca-2 and Panc02 cells (Fig.…”

Endoplasmic Reticulum Stress-Related Signature Predicts Prognosis and Drug Response in Clear Cell Renal Cell Carcinoma

“…Activation of UPR results in a decrease in the number of proteins synthesized and an increase in the extent of protein folding realized. These are achieved by regulating the UPR-related gene expression and pathways ( Nie et al, 2021 ). It has been previously reported that ER stress affects multiple aspects of cancer ( So, 2018 ).…”

Role of ERLINs in the Control of Cell Fate through Lipid Rafts

“…Thus, an increasing number of chemotherapy resistance mechanisms involved in ER stress have been discovered. ER stress-related molecular markers, such as GRP78, PERK, IRE1α, have been reported to have prognostic values for cancer patients [124].…”

“…Since aberrant UPR and ER stress are major contributors to cancer development, chemoresistance, and poor prognosis, there has been strong interest in clinically influencing this process as a strategy to restrain tumor growth and reverse drug resistance. Overall, generation of high-quality small molecules to modulate ER stress or to target the UPR, either as a monotherapy or in combination with chemotherapy, targeted therapy, and immunotherapy have shown promising preclinical treatment efficacy and offering the opportunity to develop therapeutics for a vast range of ER stress-related diseases [124,125].…”