Regulation of tumor–stroma interactions by the unfolded protein response

Abstract

The unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach.

Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells

“…In addition to intrinsic aggressiveness of the GBM cells, the brain tumor microenvironment, that contains among others endothelial and immune cells, is emerging as a crucial regulator of brain cancer progression (Obacz et al, 2017a;Quail and Joyce, 2017). The most abundant immune cells in GBM microenvironment are tumor-associated macrophages and microglial cells that might reach up to 30% of the tumor mass and have been often linked to disease aggressiveness (Bingle et al, 2002;Hambardzumyan et al, 2016;Obacz et al, 2017b;Wei et al, 2013); however, brain tumors are also infiltrated by other immune cells such as myeloid dendritic cells (DCs), plasmacytoid DCs, T cells and neutrophils (Quail and Joyce, 2017).…”

“…As such, the UPR has emerged as an adaptive mechanism supporting tumor progression and resistance to treatment by impacting almost all cancer hallmarks (Urra et al, 2016). Mounting evidence also suggests that UPR shapes tumor microenvironment by regulating angiogenesis, inflammation and host immune response (Logue et al, 2018;Obacz et al, 2017b).…”

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

“…S4E). Since the endoribonuclease responsible for XBP1 mRNA splicing (IRE1) and XBP1 have previously been involved in cytokine synthesis in immune cells and animals subjected to restrictive diets (24,25) or in cytokine release by cancer cells (26,27), we analyzed their role in cytokine synthesis. The use of a chemical inhibitor of IRE1α RNase activity, MKC-8866, prevented XBP1 splicing, but not CXCL8 induction (Fig.…”

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

“…Stromal cells play important roles in all stages of tumor development, growth, vascularization, and metastasis (6). They also must respond to similar stresses and challenges as cancer cells (7), and purportedly can achieve this by regulating protein synthesis (8), although data explicitly demonstrating this are lacking. It is thus imperative to understand whether modulating translation in cells of the TME affects cancer progression and metastasis, especially considering that anticancer agents targeting translation are currently in clinical trials (2).…”