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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 Highlights: Redox tolerance is more potent in cancer cells compared with normal cells."Transient" exposure to either oxidative or antioxidative loading is effective in disrupting redox tolerance in tumors.Tumoral cells withstand complex metabolic challenges (tensions) by exploiting various modalities including metabolic flexibility, plasticity, adaptation, fitness, addiction, competition, and symbiosis, enabling them to maintain metabolic and redox homeostasis and survive and proliferate (tumor growth).Mitochondria link metabolic reprogramming positively with redox tolerance and cancer metastasis.Metabolic interrelations between tumors with their nearby stroma suggest that nearly all cells within the TME possess the potential to reprogram metabolically.Improving the metabolic fitness of effector T cells along with their functionality and longevity are considered effective for enhancing the efficacy of immunotherapy. Glucose restoration to a therapeutic range is promising for this purpose. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that leads to disability in middle‐aged individuals. High rates of apoptosis and inappropriate homing are limitations for the application of stem cells in cell therapy. Preconditioning of bone marrow mesenchymal stem cells (BMSCs) with stromal cell‐derived factor 1α (SDF‐1α), also called C‐X‐C motif chemokine 12 (CXCL12), is an approach for improving the functional features of the cells. The aim of this study was to investigate the therapeutic efficacy of intranasal delivery of SDF‐1α preconditioned BMSCs in the cuprizone‐induced chronically demyelinated mice model. BMSCs were isolated, cultured, and preconditioned with SDF‐1α. Then, intranasal delivery of the preconditioned cells was performed in the C57BL/6 mice receiving cuprizone for 12 weeks. Animals were killed at 30 days after cell delivery. SDF‐1α preconditioning increased C‐X‐C chemokine receptor type 4 (CXCR4) expression on the surface of BMSCs, improved survival of the cells, and decreased their apoptosis in vitro. SDF‐1α preconditioning also improved CXCL12 level within the brain, and enhanced spatial learning and memory (assessed by Morris water maze [MWM]), and myelination (assessed by Luxol fast blue [LFB] and transmission electron microscopy [TEM]). In addition, preconditioning of BMSCs with SDF‐1α reduced the protein expressions of glial fibrillary acidic protein and ionized calcium‐binding adapter molecule (Iba‐1) and increased the expressions of oligodendrocyte lineage transcription factor‐2 (Olig‐2) and adenomatous polyposis coli (APC), evaluated by immunofluorescence. The results showed the efficacy of intranasal delivery of SDF‐1α‐preconditioned BMSCs for improving remyelination in the cuprizone model of MS. [ABSTRACT FROM AUTHOR]

Mitogen‐activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal–epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular‐signal‐regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross‐talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase‐2, transforming growth factor‐β, NOTCH and (in particular) with phosphatidylinositol 3‐kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK‐targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre‐evaluation of cancer‐type‐specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need. Highlights: ●Mitogen‐activated protein kinase (MAPK) pathway consists of different kinases that their interactions promote cancer initiation, growth, and metastasis.●Amplifications and mutations of up‐ and downstream kinases along with epigenetic silencing of kinase suppressors occur commonly in cancer and are associated with rebound MAPK activation and therapy resistance. Aberrant activation of MAPK pathway and therapy failure also occur due to existence of negative feedback loop of interactions between the kinases along with MAPK interactions with tumor promoting signaling pathways including transforming growth factor‐β, cyclooxygenase‐2, WNT, NOTCH, and particularly with phosphatidylinositol 3‐kinase.●To make a durable anti‐tumor response, a preferred strategy is to use combination therapy (rather than monotherapy) using different kinase inhibitors along with chemo‐ and/or immunotherapy. [ABSTRACT FROM AUTHOR]