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Published online 23 May 2008 | Nature | doi:10.1038/news.2008.855
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Stamp out common virus to beat brain cancer
New strategy could help beat tenacious brain tumours.
Cancer experts have suggested a new way to tackle particularly tenacious brain tumours known as glioblastomas. Attacking a common virus often found in these cancers may halt their growth, say researchers.
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Once someone is infected with a pathogen, in this case a herpes virus, the body will respond by activating the innate immune system. The involved cells are dendritic cell, T cells and macrophage cells. The pathogen, herpes virus or bacteria has evolved ways to hide or suppress the innate response. The PPAR, peroxisome proliferator-activated receptor, is responsible for communicating with the adaptive immune response. It is possible to heighten the metabolic signals of the innate immune system by over expressing PPAR with nicotinic acid (niacin). The increase volume from the innate immune system will initiate the adaptive immune response. The adaptive immune system recognizes and eliminate foreign invasion. The transition to an activated adaptive immune response will take between 6 to 9 months. It is important to know, while taking niacin to over-express PPAR, not to take any drug or agents whose actions include suppression of transcription activities. PPAR complement genes are sensitive to suppression. Without the PPAR complement genes the adaptive immune system will not become activated. Suppression drugs are anti-viral agents, including lysine. Once the adaptive immune system achieves activation then there will not be a need to take antiviral drugs. It will eradicate any pathogen whether viral or bacterial infection. If you decide to verify the regiment then I ask of you, after 9 months, to share your experience. There will be an outbreak each 28-days cycle for 6 months. Afterward the adaptive immune will become involved and the infection will be eliminated. The person could not consume nuts- no nuts for 9 months. The process will take 6 months to increase the metabolic signal from the innate immune system then another 6 to 12 months for complete coverage from the adaptive immune system. This chronic infection will end! Sincerely, Norman A. Smith
The emergence of cancerous cells starts in a hypoxic and nutrient-poor environment. Usually, prolonged exposure to chronic inflammation is the initial insult. By adversely, changing the cellular environment, it subsequently erodes the cell membrane. If a breach were to occur in the lipid-bilayer, it would trigger activation of cytokines, chemokines, inflammatory enzymes, matrix proteases, growth factors, angiogenic factors and survival genes. As the environmental conditions worsen, such as acidosis or necrotic debris, selected mutations and alterations will increasing occur along key growth-control pathways and downstream effectors molecule. It will develop into a concerted, orchestrated response to ensure cell growth and survival. The totality of the cell response is as if all actions and inactions (or qubits) are part of a quantum algorithm that access and initiate processes, with the interacting forces manipulating tempo. However, it is still a programme that is driven by clues or lack thereof from cell membrane receptors and nuclear receptors. To change the pathological behavior of cells, it is important to provide corrective information. A constant, overwhelming stream of data or signals that is directed toward selected targets will have the same impact to change cellular behavior as does those signals of hypoxia or lack of amino acids and glucose. Targeting GPR and PPARï�¡ï€ for continuous over-expression, using a g-agonist and nicotinic acid respectively, will initiate the process to arrest unchecked growth and proliferation. Continuous signaling to GPR, by a g-agonist with broad sensitivity, will re-generate the mucosal barrier which provides protection to the lipid-bilayer, glycophorin-A dimers and electrostatic potential. Conferring protection from strong hydrophilic forces will make possible for a member of the integrin family to bind VEGF and reverse VEGFR2 disassociation with VE-cadherin. The re-associated complex will begin to inhibit Src kinase tyrosine phosphorylation of other junction proteins (ï�¢ï€catenin, p120-catenin and ï�§-catenin/plakoglobin). As cell-to-cell junction matrix reassemble, it will halt epithelium-mesenchymal transition or permeability. The reconstitution of the cell membrane and mucosal barrier will make possible the operations of activated GTPase and phosphoinositides, and the resumption of transduction and cargo transport activities through Ras, PI(3)K, and mTOR. In turn, this will suppress activation of HIF, NF-ï�«B and support PTEN regulation to inhibit phosphorylation, of substrates involved in tumor growth, regulated by AKT. In turn, inhibiting AKT activation will restore GSK-3 phosphorylation and mTOR regulatory activities. The continuous, over-expression of PPAR and complement genes, by nicotinic acid, will restore lipid metabolism, improve insulin sensitivity and activities, increase ROS impact on TNFï�¡ to induce apoptosis, and enhance the activities of ubiquitin-proteasomes system thus relieving endoplasmic reticulum stress for normal functions. PPAR and complement genes activities will also restore the expression of gene PGC-1ï�¡ and suppress genes activated by HIF and NF-ï�«B pathways, perhaps by increasing level or sensitivity of RISC. As glucose and lipid metabolism moves to normal rate, the need for glycolysis metabolism will collapse. Those proteins that were altered or mutated by HIF and NF-ï�«B pathways will be tagged for transport to ubiquitin-proteasomes system. If the initial inflammation is resolved then the increase nitric oxide level will correct the innate and adaptive immune response, and immune cells trafficking will normalize with a restored actin-cytoskeleton. Normal cell growth and proliferation occur because of appropriate signals through cell membrane receptors and nuclear receptors which are the same receptors streaming signals for tumor growth and cancer. What becomes evident, in developing a strategy, is to change the quality of signals. It is paramount to provide positive, corrective signals that will progressively morph altered and/or mutated pathways back to norm. Evolution has proven it to be a process to achieve normal cell noise (extrinsic and intrinsic), homeostasis and the retirement of its survival algorithm. Sincerely, Norman A. Smith
Is it possible that the herpes virus has the capacity to 'mute' the normal immune response in mucocutaneous cells, but not in normal type skin cells, on one's back for example? Is it possible that even after years of recurring and increasing herpes outbreaks, an immune response could be initiated by using the unattenuated virus from an active viral site, on the 'tougher' more resistant cells on the back? Doing a smallpox type scratch innoculation. If this 'quick and dirty' method would work, there are others without brain tumors who could benefit. Has anyone looked at the immune response different areas of skin inspire? Or have locations always been choosen to avoid scarring?
"Nobody is certain whether the virus triggers the cancer or the cancer attracts the virus" - I would be inclined to believe that the virus triggers the cancer. This is not the first time that a virus has been associated with a cancer. Human papillomaviruses being the most notable in cervical cancer. Cancer is caused by a number of genetic changes - a cascade - the final step of which is cancer. The viruses could possibly cause this cascade to happen. Fight the virus and you fight the cancer. I also read that the HPV vaccine is only useful before an infection takes place. This is the portion I find perplexing - hence my doubts about its correctness. If we fight the virus then we resist the cancer causing cascade. Thus even after infection it should help.
To moderator: The greek symbols used in my comment did not translate...unless you are able to correct the error then please, do not post. Sincerely, Norman A. Smith
Siento expresarme solamente en español, pero es el unico idioma que conozco lo suficiente para no cometer errores. La cuestion es que, habiendo una demostrada relacion entre unos determinados virus y unos determinados tipos de cancer, ¿como es posible que no todas las personas infectadas por esos virus enfermen de esos canceres? ¿Podria ser que los virus se limiten a ser huespedes de otros virus o substancias aun no descubiertos y que sean estos ultimos los que causen mas directamente la enfermedad? ¿Porque detenerse en los virus y no ahondar mas? Un saludo.
Dear Mitchell, Could you not help Senator Robert Kennedy with this Immunotherapy programme as it seems very encouraging? Personally I am not in favour of Chemoradiotherapy for Glioblastoma. Regards, Salim. Prof.K.A.Salim.
Data is too preliminary. Several questions arise: What is meant by delaying tumor growth? Does that mean the tumors didn't disappear? What was the inclusion criteria? What other drugs are these people on? Did they have previous surgery? If the findings hold up, however, then this is great news. But even still, this definitely does not mean CMV causes glioblastomas. It could mean, for one example, that CMV has altered expression in tumor cells, similar to many other factors with altered concentrations in tumors. In this hypothesis, the immune cells used in this study that are exposed to CMV aren't killing the virus when injected, they are killing tumor cells expressing viral components. CMV components would just provide a unique target for the therapeutic cells, but not have any active role in tumor formation or spreading. So, under this hypothesis, antiviral therapy would do nothing for these tumors. Are brain tumors common in immunocompromised people with CMV infections? Also, if one type of virus is present, there could be others. You only see what you look for. It's refreshing that someone looked at exogenous causes for glioblastoma. Let's hope this is published soon and furthers our goal of stopping this tragic disease.
Dear Dr. Mitchell, we have found similar results for neuroblastoma. And Dr. Cobbs is very much right that immune-suppressed area like tumor is a very good niche for HCMV. I can not say whether this virus causes neoplasia, but this virus certainly loves to get associated with glioma and neuroblastoma. Interestingly, although this virus stops replication of primary cells as reported by Dr. D. Spector, it does not cause cell cycle arrest of neoplastic cells. Moreover, HCMV seems to make these tumors resistant to multiple drugs, including anti-viral therapies. So, it may not be that easy to control this virus. Thankfully, we are on the verge of developing a drug that specifically kills these tumor cells, whether infected or not, leaving out normal cells. Unfortunately, this drug has a low diffusion and tissue penetration and therefore needs to be administered in or very near to the tumor. I would love to receive opinions of experts whether this is feasible for brain tumors or not. Ananda Mookerjee, C. Davrinche team INSERM, U563, Purpan, France anandamookerjee@yahoo.com