Redox tolerance and metabolic reprogramming in solid tumors

Abstract

Tumor cells need to cope with the host environment for survival and keep growing in hard conditions. This suggests that tumors must acquire characteristics more potent than what is seen for normal tissue cells, without which they are condemned to disruption. For example, cancer cells have more potent redox tolerance compared with normal cells, which is due to their high adaptation to an oxidative crisis. In addition, increased demand for bioenergetics and biosynthesis can cause a rise in nutrient uptake in tumors. Utilizing nutrients in low nutrient conditions suggests that tumors are also equipped with adaptive metabolic processes. Switching the metabolic demands toward glucose consumption upon exposure to the hypoxic tumor microenvironment, or changing toward using other sources when there is an overconsumption of glucose in the tumor area are examples of fitness metabolic systems in tumors. In fact, cancer cells in cooperation with their nearby stroma (in a process called metabolic coupling) can reprogram their metabolic systems in their favor. This suggests the high importance of stroma for meeting the metabolic demands of a growing tumor, an example in this context is the metabolic symbiosis between cancer‐associated fibroblasts with cancer cells. The point is that redox tolerance and metabolic reprogramming are interrelated, and that, without a doubt, disruption of redox tolerance systems by transient exposure to either oxidative or antioxidative loading, or targeting metabolic rewiring by modulation of tumor glucose availability, controlling tumor/stroma interactions, etc. can be effective from a therapeutic standpoint

Enriched cancer stem cells, dense stroma, and cold immunity: Interrelated events in pancreatic cancer

“…[ 43,48 ] Disruption of the redox tolerance in tumor cells and reducing the oxidative crisis in normal cells by transient exposure to antioxidants are the suggested strategies in this context. [ 49 ]…”

“…[43,48] Disruption of the redox tolerance in tumor cells and reducing the oxidative crisis in normal cells by transient exposure to antioxidants are the suggested strategies in this context. [49] Chronic inflammation and chronic hypoxia, as discussed, are other abnormalities in the tumor area causing CSC enrichment, desmoplastic aggregates, and tumor resistance to immunotherapy, and the suggested strategy is the normalization (rather than disruption) of tumor hypoxia. An effective approach is presumed to be the targeting of TGF-β due to the key link between this signaling with the dense tumor stroma, the induction of both chronic hypoxia and chronic inflammation, and the CSC resistance to immunotherapy.…”

Normalization in tumor ecosystem: Opportunities and challenges

“…Signaling and factors that play major roles in tumor promotion are transforming growth factor (TGF)‐β (Majidpoor & Mortezaee, 2021c), vascular endothelial growth factor (VEGF) (Mortezaee, 2019), and extracellular‐signal‐regulated kinase (ERK) (Najafi, Ahmadi, et al, 2019). The nuclear factor of κB (NF‐κB) is a master regulator of inflammation and a tumor promoter, while pro‐inflammatory cytokines, such as interferon‐gamma (IFN‐γ) are generally considered as tumor suppressors (Mortezaee, 2020b; Mortezaee, Najafi, et al, 2019). Factors like adenosine, kynurenine, and lactate, and conditions like acidosis and hypoxia are playing immunosuppressive roles in TME.…”

“…Altered metabolism is considered a major hallmark in tumorigenesis. Changeable metabolism is involved in regulation of key processes related to the proliferation of tumor cells and their further migration and invasion (Missiroli et al, 2020; Mortezaee, 2020b). The metabolic abnormality that exists within the tumor ecosystem may lead to an unwanted or even deadly event called cachexia (Flint et al, 2016).…”

“…By contrast, immune cells (in particular, antitumor T cells) have limited nutrient acquisition from tumor stroma (Renner et al, 2017). A capacity that is developed in solid tumors is a shift in their metabolism based on the materials available in TME (Mortezaee, 2020b). Due to the unique leaky characteristic of tumor vasculature, the amount of nutrients in the ecosystem of tumor is insufficient to meet the demands of a growing tumor that contains a complex pack of heterogeneous cell types (Majidpoor & Mortezaee, 2021a).…”