those stress responses in tumors

Hello everyone, today I will share with you two important stress responses in tumors: Endoplasmic reticulum stress and oxidative stress.
Interested friends listen carefully! 1.
Endoplasmic reticulum stress in cancer Protein processing, modification and folding in the endoplasmic reticulum (ER) are closely related regulatory processes that determine cell function, fate and survival
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In many cancers, diverse oncogenic, transcriptional, and metabolic abnormalities combine to create an unfavorable microenvironment that disrupts endoplasmic reticulum homeostasis in malignant and stromal cells, infiltrating leukocytes
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These changes trigger a persistent state of ER stress (endoplasmic reticulum stress, characteristic: accumulation of misfolded or unfolded proteins) that has been shown to control multiple tumor-promoting properties in cancer cells while dynamically Reprogramming the function of innate and adaptive immune cells
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Thus, aberrant activation of ER stress sensors and their downstream signaling pathways has emerged as a key regulator of tumor growth and metastasis as well as responses to chemotherapy, targeted therapy, and immunotherapy
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Common drivers of endoplasmic reticulum stress in the tumor microenvironment The uncontrolled proliferative capacity of tumor malignant cells in growing tumors creates an unfavorable microenvironment characterized by high metabolic demands, hypoxia, nutrient deficiencies, and acidity Intoxication, which in turn disrupts calcium and lipid homeostasis in the multiple cell types that inhabit this environment
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Collectively, these harsh conditions alter the protein-folding capacity of the endoplasmic reticulum (ER) in cancer cells and infiltrating immune cells, promoting the accumulation of misfolded or unfolded proteins within this organelle, thereby promoting the ER stress
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Oncogenic events in cancer cells further promote this state by increasing their overall transcription and translation rates
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The unfolded protein response (UPR) is subsequently activated in an attempt to restore ER homeostasis and facilitate adaptation to various lesions in the tumor
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Certain therapeutic modalities can also trigger endoplasmic reticulum stress in cancer cells, thereby altering their normal behavior in the tumor microenvironment (TME)
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Depending on the degree of ER stress, cell type, and specific pathological context, ER stress responses can have a variety of effects, ranging from cellular reprogramming and adaptation to autophagy and apoptosis
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The accumulation of various ER stressors enriched in the TME and the phenomenon of robust and sustained UPR activation during cancer development, progression, and therapy have been demonstrated in cancer cells and tumor-infiltrating immune cells in vivo
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Ref: PMID: 33214692; IF: 60; Nat Rev Cancer2, Endoplasmic reticulum stress response in cancer cells Coordination of the endoplasmic reticulum stress response is a highly dynamic process
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Persistent but modest endoplasmic reticulum (ER) stress responses driven by oncogenic pathways, metabolic changes, and tumor microenvironmental conditions stimulate several mechanisms that promote cancer cell proliferation, metastasis, chemoresistance, angiogenesis, and immune evasion
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In contrast, extreme ER stress due to the uncontrolled accumulation of misfolded proteins in this organelle can lead to the ultimate unfolded protein response (UPR), which induces cell death
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Cancer cell fate determination appears to depend on the strength and duration of the UPR
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Canonical roles of the unfolded protein response (UPR): sensing and responding to endoplasmic reticulum stress 3, integration of the oncogenic program in tumor cells and the endoplasmic reticulum stress response Oncogenic MYC activates the unfolded protein response (UPR) through multiple mechanisms: MYC-induced upregulation of global transcription and translation increases ribosome biosynthesis and protein loading in the endoplasmic reticulum (ER), which activates all branches of the UPR; MYC can also interact with activated transcription factor 4 (ATF4) to Regulates amino acid transporters and biosynthesis, antioxidant pathways, and autophagy; MYC can also form heterodimers with X-box-binding protein 1s (XBP1s) in the nucleus to regulate canonical UPR genes and lipid metabolism genes
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Activation of mTOR complex 1 (mTORC1) induces protein synthesis and ER overload, thereby activating the UPR
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RAS mutations integrate UPR processes in a context-specific manner; 4.
Intratumoral immune cells UPR-responsive cancer cells regulate natural killer (NK) responses to tumor cells upon activation of inositol-requiring protein 1α (IRE1α) or PRKR-like ER kinase (PERK) , while secreting mediators that promote angiogenesis and the recruitment of myeloid cell types to tumor sites
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Both IRE1α and PERK can well regulate angiogenesis
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Myeloid-derived suppressor cells (MDSCs) utilize PERK to control antitumor immunity, and endoplasmic reticulum stress in MDSCs is also associated with increased expression of tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) and in the TME.
of quick turnaround
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Endoplasmic reticulum-stressed neutrophils acquire immunosuppressive properties and overexpress LOX1 through IRE1α activation
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ROS accumulation promotes ER and persistent IRE1α–XBP1 activation in tumor-associated dendritic cells (DCs), while inhibiting their ability to present local antigens to intratumoral T cells
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It has been shown that overproduction of the immunosuppressive lipid mediator PGE2 via IRE1α-XBP1 activation may contribute to immune escape in cancer
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In macrophages, the IRE1α–XBP1 branch has been shown to promote the expression of cathepsin, PD1 ligand 1 (PDL1), and arginase 1, further promoting cancer cell invasion and immunosuppression in the TME
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Pharmacological regulation of the UPR Various standard anticancer treatments can induce endoplasmic reticulum (er) stress and activate the unfolded protein response (uPr) in malignant cells as an adaptive pro-survival mechanism
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Chemotherapy resistance (UPR) is associated with chemotherapy response in human breast cancer
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High bound immunoglobulin (BiP) expression is associated with shorter recurrence-free survival in breast cancer patients receiving adjuvant doxorubicin
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BiP inhibits BaX by and caspase 7 activation to inhibit doxorubicin-induced apoptosis)
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Hormone therapy resistance (in breast cancer, BHPi activates the UPR by activating phospholipase Cγ and depleting calcium stores to inhibit protein synthesis, and BHPi enhances the cytotoxic effect of endocrine therapy by inducing a lethal stress response in these cancer cells)
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Targeted therapy resistance (BraFi and MeKi inhibitor combinations are the standard of care in BraF-mutant melanoma and lung cancer, treatment with these inhibitors results in MaPK-dependent translocation of seC61 into the endoplasmic reticulum, leading to PerK-mediated erK rephosphorylation ization and reactivation)
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I believe that through the above description of endoplasmic reticulum stress, everyone must have a preliminary understanding of ER
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If you are careful, it is not difficult to find that ER is indirectly or directly related to a variety of current hotspots, such as hypoxia and apoptosis.
I believe that everyone has paid much attention to it; for example, the increase of reactive oxygen species ROS will cause ER, It is also one of the main features of iron death
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When it comes to ROS, let’s talk about our next knowledge point: oxidative stress 2.
Oxidative stress in cancer Oxidative stress (OS) refers to the production of biological cells in the body when they encounter various stimuli.
High levels of highly active substances, such as reactive oxygen species, nitrogen free radicals, etc.
, lead to an imbalance in the rate of oxidation-reduction reactions in the body, and the oxidation rate caused by various oxides exceeds the body's antioxidant capacity, resulting in oxidative stress damage to the human body organization
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The essence of oxidative stress is a state of imbalance of oxidation-antioxidation in vivo (Ref: PMID18421291; IF: 15+; Nat Chem Biol)
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It is a negative effect produced by free radicals in the body, and is considered to be an important factor leading to aging and disease, as well as a major cause of tumors and a series of other diseases (Ref:PMID8108730; IF:47+;Science)
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Oxidative stress is two-sided: while excessive oxidative attack causes damage to biomolecules, maintaining physiological levels of oxidation, termed physiological oxidative stress (Eustress), is necessary to control life processes through redox signaling
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The role of oxidative stress in the occurrence and development of tumors Relevant basic scientific research shows that almost all tumor cells have an imbalance of the intracellular oxidation-reduction system.
The imbalance of the reduction system directly leads to tissue damage.
On the other hand, it can also lead to oxidative modification of amino acid residues, resulting in DNA mutations, esters and changes in the spatial structure of proteins.
The final result is a series of pathological changes
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The imbalance of this system can be found in various pathophysiological processes such as cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cancer occurrence and body aging.

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 Reactive oxygen species can cause DNA damage and mutation, and the types of mutation include point mutation, sequence deletion, insertion and chromosomal translocation, cross-linking and so on
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Direct DNA damage or genomic instability, gene expression and protein conformational changes all play a role in the development of cancer
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The result will mediate the activation of proto-oncogenes or the inactivation of tumor suppressor genes, and the changes of genes will lead to abnormal cell proliferation and form tumors (Ref: PMID15763963; IF: 4+; Free Radic Res)
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High levels of oxidative stress are cytotoxic and can induce apoptosis or necrosis
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But if low levels of oxidative stress persist, cell division and tumor growth are prone to occur
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Reactive oxygen radicals lead to the process of tumor production, and have a certain effect-dose-response relationship
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Acute and high concentrations of ROS lead to cell apoptosis and necrosis by oxidative stress leading to structural changes in proteins, lipids and even DNA; relatively moderate concentrations of ROS temporarily or even permanently cause cells to arrest at a certain level during their division cycle.
A series of physiological reactions lead to the final differentiation of cells; chronic, low-level ROS can promote cell mitosis and cause cell proliferation, and increase the genomic instability in new cells, which can induce tumorigenesis and development
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Studies on breast cancer, thyroid cancer, gastric cancer, etc.
have shown that the level of oxidative stress in tumor patients is significantly higher than that of normal people, and the level of antioxidant enzymes is significantly lower
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It can be seen that there is a higher level of oxidative stress in the tumor patients than in the normal physiological population
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Oxidative stress and tumor therapy Although a large number of studies have shown that highly active molecules can promote tumor formation and development, highly active molecules can also play an important role in the anti-tumor process
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Studies have shown that acute and high concentrations of ROS cause cell apoptosis and necrosis through oxidative stress leading to structural changes in proteins, lipids and even DNA
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Under the same concentration of ROS, normal cells can tolerate it, while tumor cells tend to be more prone to ROS due to three factors: higher intracellular ROS concentration, unstable cell structure, high susceptibility to ROS, and defective oxidative stress defense system.
Apoptosis and necrosis
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Professor Huang HL et al.
found that carboplatin activates the membrane death receptor Fas (APO-1) pathway by inducing high levels of ROS, and ultimately promotes cell apoptosis (Ref: PMID14603257; IF: 9+; Oncogene)
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Prospects of oxidative stress The imbalance of the oxidation-reduction system can cause cytotoxicity and lead to tumor cell apoptosis and even necrosis
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Different concentrations of reactive oxygen species have different effects on cells, and the same concentration of ROS for different time periods has different effects on cells
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How to rationally adjust the level of reactive oxygen species produced by the body by rationally adjusting the use of antioxidant enzymes in tumor prevention and treatment, the application of tumor suppressor drugs, the selection of radiotherapy ray waveforms and the setting of irradiation duration, so as to improve their effect on tumor cells.
It will become the latest direction of future research on tumor prevention and treatment while reducing its killing effect on normal tissue cells
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Elucidating the oxidative stress levels of different tumors and different stages of the same tumor is also of great significance for exploring new theories of tumor antioxidant therapy
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 Today's sharing is over, I hope it will be helpful to everyone's scientific research
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The vice push is a pure tumor research article on the two directions of endoplasmic reticulum stress and oxidative stress.
If you want to know more about it, don't miss it
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