How is the Immune System Suppressed by Cancer - 1 views
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nitric oxide (NO) released by tumor cells
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Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
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NO from eNOS in cancer cells can travel through membranes and over long distances in the body
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NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
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The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
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nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
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Inhibition of inducible Nitric Oxide Synthase (iNOS)
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NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
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Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
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tolerance in the immune system that decreases the immune response to antigens on the tumors
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Freund’s adjuvant
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increase in kinases in these cells which phosphorylate serine, and tyrosine
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responsible for activation of many growth factors and enzymes
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phosphorylated amino acids suppress iNOS activity
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Hexokinase II
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Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
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Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
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Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10. IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
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Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
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These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
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Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
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Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
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IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
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IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
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nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
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NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
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early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
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later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
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cGMP is increased by NO
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NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
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the greater the malignancies and the greater the metastatic potential of these tumors
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The greater the NO production in many types of tumors,
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gynecological
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elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
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The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells. Histamine alone stimulates many tumor cells.
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The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
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T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
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last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
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intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
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In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
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Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
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Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
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Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
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Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
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COX 2 inhibitors or all trans-retinoic acid
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Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
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interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
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In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
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these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
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Great review of the immunosuppression in cancer driven by the likes of NO.