Francis Peyton Rous challenged the oncology world first when he suggested that tumors and cancers did not spontaneously occur but could be triggered by something in a contagious way. He could see that he was transferring some agent from one chicken to another and triggering tumors. Unbeknownst to him he was working with the Rous Sarcoma virus. (when the virus was discovered it was named after him) The oncology world seemed to believe that this was strictly a chicken pattern. Unsuccessfully he alone attempted to isolate this and other viruses from mammalian tumors for years.
In 1933 fellow researcher Richard Shope finally isolated a virus the HPV from mouse tumors. They now had a virus. Fervently Rous and his coworker Friedewald studied the HPV virus attempting to prove that this virus triggered the tumors in mammals.
Rous and Shope then joined forces and went on to demonstrate that cold tar could synergistically with a rabbit papilloma virus cause squamous cell cancers. Viruses did not just cause tumors they could cause cancer. These experiments were reproduced and copied using other viruses and other carcinogens and the idea of synergism had just started to take off when I believe we became distracted with the horrific results of war. The agent orange and radioactive bombs used during the Vietnam war damaged DNA so profoundly that the world view of such cancers and birth defects completely changed. The general public and even most researchers now will say that cancer is caused by DNA damage. Co-carcinogenesis was quickly forgotten as we embraced anti-oxidants in attempts to protect our DNA from damage.
Even in the 1966 nobel prize speech Rous gave for work on HPV he expressed how most cancer was not a transformed gene from DNA damage rather from viruses but the world didn't listen.
In 2004 Harry Haverkos wrote a paper on viruses, chemicals, and co-carcinogenesis. He demonstrated for the first time in years the possible co-carcinogenesis of cervical cancer, hepatocellular carcinoma, and Kaposi's sarcoma using statistics. Co-carcinogenesis he suggested is the synergistic actions of a virus and a carcinogen together that both must be present just as Rous hypothesized.
Evaluation of Hypothesis:
Viruses are known to make proteins that interact with the telomeres which are the ends of our chromosomes. The condition of the telomeres, how frayed or pristine, determines how many times the chromosomes can be copied. Viruses are therefore making our DNA, the cookbooks of our cells, immortal and open for use. Viruses do not cause cancer alone only when a carcinogen is present.
Carcinogens
Carcinogens, such as benzene and phenols, are now known to have multiple actions including inhibiting polymerases which are the DNA readers. Viruses typically make their own polymerases which have a stronger affinity for binding in order to compete with the host's polymerase. Now imagine them coexisting as Co-carcinogenesis suggests. The DNA has been opened up but the viral polymerases are inhibited by the carcinogen and a cancer cell has been created. Is this possible?
The carcinogens inhibit cell division and growth. The carcinogens are closely linked with cancers. Fracking workers absorb high levels of benzene into their bone marrow but only show signs of anemia for years before they develop a bone marrow related cancer like leukemia. Rats given a alcohol on a daily basis had stunted growth of their limbs. Long term alcohol abuse has been linked to liver cancer in people. Teenage boys who smoked cigarettes were on average 2 inches shorter than their non smoking peers. Organochloride pesticides, like heptachlor, in maternal blood were also linked to smaller birth size.
A carcinogen alone inhibits growth. It is not DNA damage rather a synergy. As Francis Peyton Rous noticed we can observe that a carcinogen together with a virus causes cancer. Carcinogens can be linked to specific cancers because of where they go in the body. Heptachlor which can be absorbed by fat has been linked to breast cancer in Hawaii, nitrite inhalents were linked to Kapsoi's cancer in Aids patients who took them as "poppers", and cadmium which collects at the growth tips of bones has been linked to teen boys with osteosarcoma.
The virus when it enters a cell uses a specific receptor thus stimulates the production of more of those specific receptors to be made. It is my contention that when we look at the cancerous tumors they will be over expressing the receptor which tells us which virus triggered them. The characteristics of the cancer will also take on attributes of the pathway launched by the receptor.
Since there are only five virus families that infect the nucleus of cells we will attempt to divide all the cancers up into these five families: the human papilloma viruses, the Herpes viruses, the Retroviruses, the polyomaviruses, and the flaviviruses.
HPV
The human papilloma virus family use the cannabinoid receptor family of which CB1 and CB2 end up in the nucleus whereas those HPV that use the capsaicin receptor do not. The capsaicin receptor group would involve a burning sensation but not cancer.
Clear cell renal carcinoma has been connected to HPV16. HPV16 appears to use the cannabinoid one receptor which may explain the yellow to clear appearance of the cells. CB1 receptors have been tied to ceramide which can change a cells lipid metabolism. If overstimulated the cell could over produce lipids resulting in the yellow appearance of the cancer. The expression of the CB1 receptors is controversal. CB1 receptor has been found to be over expressed and under expressed in these renal tumor cells. Are they over expressed before becoming under expressed?
Cervical cancer was the first cancer linked to HPV. There are 2 forms of cervical cancer squamous and adenocarcinoma. The squamous form of has been connect specifically to HPV16 and CB1. Squamous cells have also been connected to lipid metabolism changes. The adenocarcinoma form of cervical cancer has been connected to HPV18. Adenocarcinoma is the most common type of prostate cancer where HPV18 infection is found more often and CB2 receptors have been found to influence prostate cancer.
Predictable there are exists a squamous form of non-melanoma skin cancer that was connect to HPV16 and an aggressive basal form which was connected to HPV18. Do these non melanoma skin cancers express different cannabinoid receptors? (double checking which cannabinoid receptors go with which virus)
Triple negative estrogen receptor breast cancers have been found to contain HPV. Some triple negative breast cancer are basal cells and a few rare ones are squamous in shape.
HERPES
The Herpes virus family use the estrogen receptors of which there are three types alpha, beta, and estrogen-related receptors. Only the alpha and estrogen-related receptors cycle to the nucleus. The beta estrogen receptor cycles to the mitochondria which means the alpha-herpes like herpes zoster cannot cause cancer.
EBV and HHV8 are gamma-herpes that use the alpha estrogen receptors. EBV has been linked to estrogen receptor positive breast cancers. CMV use the estrogen-related receptors like progesterone and CMV has been linked to some forms of breast cancer. There are breast cancer cells that are only progesterone positive but it remains unclear that this is the CMV group.
EBV and HHV8 has been isolated from Papillary renal carcinomas which as herpes viruses would trigger estrogen receptors.
Yuan Chang and Patrick Moore's HHV8 is also known as the Kaposi's virus. They proved that it produces the spindle like Kaposi's cancers often seen in AIDS patients. The spindle like shape occurs because some of the alpha estrogen receptors stimulate luteinizing hormones. (which can make Kaposi's look as if they were started by retroviruses but they are not)
RETROVIRUSES
Luteinizing hormone receptors and spindle cancer cells are strongly linked to the Retrovirus family.
Chrondrosarcomas have spindle cell components of cartilage. HIV patients have increased rates of chrondrosarcoma. HIV as a retrovirus looks like it triggers spindle cells like other known retroviruses. Spindle cell sarcoma in chickens has already been documented and accepted to be caused by the Rous sarcoma virus. Rous sarcoma viruses are a type of retrovirus.
Retroviruses, like HIV, might be binding albumin-binding receptors which includes the luteinizing hormone receptor. When the luteinizing hormone is high during a female patient's cycle the level of HIV drops and the Luteinizing hormone receptor is normally overexpressed in the Theca cells of the ovary which have a spindle cells shape to them. Is the spindle shape connected to the receptor?
HIV patients not only have increased chrondrosarcoma but increased hepatic spindle tumors.
POLYOMAVIRUSES
Polyomaviruses use the serotoinin receptors.
Osteosarcomas are the most common type and largest group of bone cancers with a higher rate in African males. The JC virus, a polyomavirus, being of African origin is found in slightly higher rates in african americans. Can JC be found in osteosarcomas? Simian virus 40 specifically has been found to cause osterosarcomas in monkeys. Michelle Carbone has found sv40 in 1/3 of the human Osterosarcomas. Osterosarcomas have increased serotonin receptors supporting the notion that the receptor used by the virus to infect increases. BK viruses use serotonin receptors.
Osteosarcomas have been shown to be induced by x-rays. Both polyomaviruses and X-rays have also been linked to papillary thyroid carcinomas. Both of these cancers have been found to have abnormally high DNA levels. Interestingly serotonin has been shown to have a protective effect against X-rays and that Serotonin receptor antagonists can repair DNA after UV Damage. Apparently with extremely high does of X-ray the DNA repair state spins out of control. Polyomaviruses binding serotonin receptors apparently triggers DNA regeneration as it infects and if a carcinogen is present with the virus cancer results.
Iron binding proteins have been shown to be regulated by serotonin receptors. Which is interesting because osterosarcomas have been treated in dogs with artemisinin. Artemisinin is a component of worm wood that binds iron. This treatment of artemisinin seemed to destroy the osterosarcomas in dogs.
Hale's colloidal iron staining is the method of identifying chromophobe renal carcinomas from other renal cancers because these cancer tumors have such a high iron content.
Chromophobe renal cancer has been associated with Birt-hogg-dube because of the appearance of follicular tumors. The disease and the cancer both have extreme mitochondrial biogenesis occurring. Interestingly while the birt-hogg-dube form may be genetic the chromophobe type may be due to the triggering of serotonin receptors. The BK virus which is notorious for infecting Kidney transplants is a polyomavirus which appears to use serotonin receptors and could be the culprit here.
Meninginomas of the brain have been linked to polyomavirus sv40 and with high iron concentrations.
The endocrine pancreatic cancers such as Insulinoma, Glucogonoma, and gastrinoma duct tumors all seem to be linked to polyomaviruses. Insulinomas with BK polyomavirus, and glucogonoma with SV40.
FLAVIVIRUSES
Flaviviruses use the melanocortin receptor family. Not all of these receptors move to the nucleus only some do : MCR4 and MCR2. (trying to see if the accessory protein these 2 receptors bind has a nuclear pore code)
In Heptocellular cancer there are two mouse models. One involves a mutated MCR4 receptor creating HCC and the other are mice trangenic for the agouti protein which binds melanocortin receptors producing mice that were not just golden in color but obese with high rates of liver cancer.
Hepatitis C and yellow fever have both been found connected to heptocellular cancer tumors. Heptocellular cancers tend to be full of fat deposits. Note that leptin, the fat cell hormone, has been shown to inhibit HCC growth and the MCR4 has been shown to regulate fat consumption.
HCC has also been found to have altered glucose metabolism. The MCR2 and MCR4 receptors have been linked to glucose metabolism.
It seems likely that Hepatitis C and yellow fever use MCR4 which moves to the nucleus to regulate genes connected to fat metabolism. If a carcinogen is encountered these genes are stuck activated.
Chronic hepatitis C patients also have higher rates of hypothyroidism and thyroid papillary carcinomas which leads to a suspicion that these thyroid issues maybe partially triggered by the virus.
Note that I think there are 3 types of thyroid papillary carcinomas: irregular, cystic, and nodule. Tempted to think that the cystic is EBV, the nodule is HHV8, and the irregular and most common form is the one tied to flaviviruses but this is suspected on very little evidence. (Follicular thyroid would be the polyomavirus family because of the mitochondrial biogenesis associated with it)
Extreme Methylation Changes
Excessive DNA damage, such as damage from UV light, trigger demethylation of DNA. These 5 nuclear viruses turn on embryonic Herv genes through methylation changes without DNA damage. Only the human papilloma viruses trigger demethylation by using cannabinoid receptors. Estrogen receptors, serotonin receptors, melanocortin receptors, and luteinizing receptors all methylate the DNA.
Early embryogenesis goes back and forth through extremely high methylation and demethylation states. Think of methyl groups as stickers turning on and off genes.
Zygote - demethylation- Blastocyte- methylation- Epiblast (pluripotent cells)
awakens Herv K Herv H/ Herv F
Epiblast -demethylation - PGCs - methylation -Fetus
Herv E Herv W
When a virus uses a receptor the pathway is magnified including methylation changes which means we can see the associated Hervs. Methylation can awaken Herv H, Herv F, and Herv W. Demethylation can awaken Herv K and Herv E.
Looking at breast cancer we can see possible examples of each.
The alpha-estrogen receptors and estrogen-related-receptors cycle to the nucleus which would allow herpes viruses to interact with DNA. Both estrogen receptors and progesterone receptors methylate genes. Therefore the Herve genes seen with these estrogen and progesterone breast cancers have the embryonic genes that appear when the DNA is methylated. Syncytin-1 aka Herv W is over expressed in breast cancer. Furthermore the BCL gene is activated by methylation so these are the cancers that have the potential to metastasize.
The cannabinoid receptors have been studied as pain relievers. Methylation has been linked to the sensation of pain. Cannabinoid receptors are thought to relieve pain by demethylating. HPV has been linked to triple negative breast cancer and if they use cannabinoid receptors this could explain what is seen. Do the triple negative breast cancers involve demethylation thus explaining why Herv E can be found in some breast cancers? The Triple negative breast cancers are also faster and more aggressive which matches the state of demethylation in the embryogenesis and the DNA damaged state of ultra violet light which demethylates causing the rapidly growing melanoma.
Conclusion
Co-carcinogenesis could very well be the most common cause of cancer. The synergy between viruses and carcinogens resulting in viral polymerase inhibition, the change in methylation states, and the magnification of the receptor's pathways used by the viruses do appear to cause the characteristics of the cancer seen. Hopefully this paper has inspired experiments to be done to verify these hypotheses beyond the circumstantial evidence.
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2.
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