Title: Updating Co-carcinogenesis
Abstract: Co-carcinogenesis is the synergism between a nuclear virus and a carcinogen to cause cancer. The receptor used by the virus to enter the cell triggers either methylation or demethylation. Note that severe DNA damage causes demethylation however this co-carcinogenesis hypothesis suggests that cancer can develop merely because of extreme methylation or demethylation even if the DNA has not been damaged.
Cancer cells appear to express the receptors the viruses used to infect them. This is because when the receptors are used they are activated triggering the pathways they are linked to and then the cell creates replacement receptors. Some receptors trigger methylation while others trigger demethylation.
This is how without damaging the DNA viral infections awaken Hervs, the embryonic genes characteristic of cancer. The four stages of embryo genesis switch back and forth between methylation and demethylation. These embryonic genes set the stage for the rapid cell division seen in cancer.
In a cancer cell, the virus opens the DNA up and then can not function to destroy the cell or make new viruses because the carcinogen inhibits the viral polymerase. Polymerases are the transcription vehicles that turn the DNA cookbook into RNA recipes that can be used. The viral polymerases have probably evolved to compete with host polymerases and have stronger binding efficiencies.
It is my contention that cancer occurs because a carcinogen inhibits the viral polymerase better than the human polymerase. Alone a carcinogen would just stunt growth by binding the host's polymerase. When a virus infects the same cell as a carcinogen they interact. Instead of the virus making what it wants in the host the infected cell is transformed into a cancer cell by the carcinogen.
These hypotheses supports Co-carcinogenesis as the cause of cancer without DNA damage where it is the synergism between a carcinogen and a virus that causes cancer. Both have to be present in the nucleus of a cell.
This paper will go through several types of cancer looking at the patterns. The receptors expressed by the tumors will be matched up with the corresponding viruses and to validate the match the known methylation or lack there of will be examined. The most feasible carcinogen for each cancer will also be considered.
Introduction:
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 the 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 HPV from mouse tumors. They now had a mammalian 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.
Based on what we know today this paper will attempt to suggest possible pathways to explain the co-carcinogenesis mechanism of cancer development.
Hypotheses: Only nuclear viruses cause cancer. Cancer cells express the receptors the virus used to infect them. Carcinogens inhibit the host's polymerases until the viral polymerases are present. Which embryonic hervs that are expressed in the cancer reveals which method the virus' receptor uses: methylation or demethylation. Demethylated cancers are more aggressive. All of these hypotheses come together to support Co-carcinogenesis as the common cause of cancer.
Evaluation of Hypothesis:
Viruses are now 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. 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 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. So let's look at a few cancers and see.
(Removed Kaposi's for now)
Breast cancer
Breast cancer has three major types. An estrogen receptor positive type, progesterone receptor type, and the triple negative type. Interestingly enough three different viruses have been isolated from breast cancer; the HPV virus, the CMV virus, and the Epstein-barr virus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344231/
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972522/)
Looking first at the herpes viruses first CMV infection has been found to be estrogen-related-receptor dependent. Progesterone as an estrogen related receptor could be what CMV is using to trigger Breast cancer.
CMV and estrogen related receptor
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284536/
Progesterone is an estrogen related receptor
EBV is a gamma-herpes virus which would be using the alpha-estrogen receptor thus creating the estrogen receptor positive form of breast cancer.
The alpha-estrogen receptors and estrogen-related-receptors which some herpes viruses use cycle to the nucleus which would allow herpes viruses to interact with DNA. Further both estrogen receptors and progesterone receptors methylate genes. (think of methyl groups as stickers on the DNA helping to change which genes are expressed) 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. Normally Herv W is only awakened by methylation in embryo cells.
Zygote - demethylation- Blastocyte- methylation- Epiblast (pluripotent cells)
awakens Herv K Herv H/ Herv F
Epiblast -demethylation - PGCs - methylation -Fetus
Herv E Herv W
If the herpes virus Epstein-barr triggers the estrogen receptor positive tumors of breast cancer then the HPV virus could be the trigger of the other type of breast cancer tumor.
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.
There are 2 forms of cervical cancer squamous and adenocarcinoma. The squamous form of has been connect specifically to HPV16 and cannabinoid receptor 2. The adenocarcinoma has been connected to HPV18 and cannabinoid receptor 1. Predictable there are exists a squamous form of non-melanoma skin cancer that was connect to HPV16 and a basal form which was connected to HPV18. Do these non melanoma skin cancers express different cannabinoids?
HPV could be using cannabinoid receptors. Cannabinoid receptors are on triple negative tumors and cannabinoid treatments have been considered as a form of treatment for triple negative breast cancers. An activated cannabinoid receptor demethylate genes.
Cannabinoids inhibited cervical cancer cells migration, a known HPV cancer. Interestingly enough cannabinus oil has also been a suggested remedy for non-melanoma cancers. Non-melanoma skin cancer has associations with HPV. Non-melanoma skin cancer has increased cannabinoid receptors. Triple negative receptor breast cancers and cervical cancers should be examined for increased cannabinoid receptors.
Unfortunately the carcinogens of the skin that would interact with viruses, are applied as lotions and still available to the public. Diazolidnyl urea or iodopropynyl butylcarbamate are compounds that release formaldehyde. Formaldehyde is highly carcinogenic.
Can we connect a specific carcinogen to breast cancer?
The carcinogen has to collect at the target tissue which in this case is the breast. Heptachlor which was an insecticide of the 1980s and is still currently used on fire ants has been found to collect in the breast. Since heptachlor is not metabolized it merely collects increasing in concentration until the virus is caught. Hawaii had sprayed heptachlor on the tops of pineapples which were not for human consumption rather fed to cows. When breast cancer rates skyrocketed they realized the heptachlor was in the milk people were drinking. Although the procedure of using heptachlor on pineapples has stopped those people with heptachlor could still develop breast cancer.
Heptachlor is a type of organochloride. Organochlorides have long been suspected of triggering breast cancer but studies seem to indicate the mere collection of the compounds do not cause cancer. However Co-carcinogenesis could explain the data. Chlorine has been shown to inhibit adenovirus DNA synthesis. If chlorine inhibits the polymerase of the viruses found in the breast which are HPV and Herpes Zoster then it is highly likely that heptachlor and the other organochlorides do too.
Bone Cancers: Ewings, Osteosarcoma, Chondrosarcoma (cartilage) , Chordoma, and Fibrosarcoma
Ewings has been associated with CMV and Epstein barr. Interestingly Ewings has also been associated with the hormone swings of pregnancy which would elevate estrogen levels. As herpes viruses they would be using estrogen receptors and the tumors would have increased estrogen 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 in dozens of osterosarcomas in monkeys could JC be the human version. 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. Interesting note that serotonin has been shown to have a protective effect against X-rays.
Are X-rays the carcinogen or do x-rays somehow destroy the same path way?
X-rays and serotonin
https://www.karger.com/Article/Pdf/254512
Cadmium is a possible carcinogen for bones because it collects at the growth tip of the bones and has strong associations with the cancer. Further because teen boys tend to grow rapidly and taller than girls they would have more cadmium added which could explain why they have higher rates of bone cancers. Occupations dealing with cadmium have higher rates of osteosarcoma and heavy metal implants have been found associated with sarcomas. Cadmium is found in cigarettes, and cigarette smoke. Cadmium can be found with fertilizers and in Africa the cadmium has been found to contaminate the hot chocolate of Africa because of this. Cadmium has also been found in shellfish and oysters in high levels which could explain the clusters of cases in the northeast coast. Toxic levels of cadmium were also dumped into Tampa Bay in 2011 and there are clusters there too. Osterosarcoma case clusters should appear near high cadmium areas.
Cadmium can inhibit DNA polymerases directly. This fits with our theme of a carcinogen present at the site which can inhibit the viral polymerases.
Cadmium has also has been linked to Chrondrosarcomas.
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.
What carcinogens appear with these spindle tumors?
Pancreatic cancer
How about pancreatic cancer? There are 2 major types of pancreatic cancer, exocrine and endocrine.
Endocrine cells secrete enzymes into the bloodstream whereas exocrine cells secrete into the intestine. The exocrine form is the most common so this must be a common virus. There seem to be multiple types of endocrine cancers which might match up with the different viral infections.
First the endocrine pancreatic cancers such as Insulinoma, Glucogonoma, and gastrinoma duct tumors all seem to be linked to polyomaviruses. Insulinomas with BK polyomavirus, glucogonoma with SV40, and gastrinoma with Hepatitis B.
Again, Polyomaviruses use the serotonin receptors to infect cells and these receptors seem to be increased in these endocrine pancreatic cancers. Hepatitis B is sort of strange in that it is not really a polyomavirus and tends to act like a retrovirus using reverse transcription.
The most common pancreatic cancer, adenocarcinomas, are the exocrine cancers. Squamous adenocarcinomas has been connected to HPV16. Both cannabinoid receptors exist on the pancreas. Again HPV16 uses CB2 while HPV18 uses CB1. Is it possible that the most common form of pancreatic cancer is caused by HPV18?
2/3 of pancreatic cancers occur in alcoholics. Alcohol does inhibit polymerases and could easily inhibit a viral polymerase. The other pancreatic carcinogen could be N-nitros also known as nitrates or nitrites in foods. Highly processed foods like meat, cheese, and beer have high quantities and it's impact has been questioned. Viral polymerases can be inhibited by nitrogen oxides which nitrates and nitrites are and this feature fits with the co-carcinogen hypothesis.
When we look for carcinogens of the brain the alcohol and benzodiazepine are the most likely candidates. Again, alcohol can and does inhibit polymerases contributing to the stunting of growth and likely inhibits viral polymerases if they are there. Benzodiazepine which is an anxiety medication can be absorbed into the fats in the brain when in high concentrations. Benzodiazepine has be proven to inhibit the polymerases of Hepatits C specifically. The benzene ring of the these medications could be what inhibits the viral polymerases when alcohol is not involved. This is a side effect of an anxiety drug.
Acyclovir is a medicine prescribed for it's ability to inhibit the polymerase of herpes viruses and is currently used as a treatment to stop viral infections. There are cases where herpes encephalitis was diagnosed, acyclovir was prescribed and then the patient was discovered to have gliomas tumors. The question is were they misdiagnosed or did the viral infections become high grade glioma tumors. Acyclovir is not consider carcinogenic because when fed to rats and mice log term no tumors developed. What if the rats had herpes infections at the same time? The reason that acyclovir does not cause cancer in shingles patients has to do with where the virus is. Herpes viruses use estrogen receptors. The estrogen receptors of nerves cycle to the mitochondria and use the mitochondria's little DNA. Cancer only occurs when the virus is at the nuclear DNA which is the huge cookbook. In the breast or in the glial cells of the brain acyclovir would be a carcinogen and should never be used in those cases.
Gliomas, brain cancers of glial cells, are also associated with Alzheimer's disease. If some forms of Alzheimer's are due to a herpes virus infecting and destroying a neuron's mitochondria then gliomas would the herpes virus infecting the nucleus of the glial cells when the carcinogen such as nitrates was there. The overlap of the gliomas and Alzheimer's is the herpes virus. Herpes simplex virus encephalitis has been found in glioma patients. Cmv has also been connected to gliomas especially in children. Herpes zoster has been connect to gliomas too. With all the connections to herpes viruses it is not surprising that some gliomas express estrogen receptors.
Meningiomas, the brain cancers of the meninge cells, are associated with polyomaviruses like sv40 in monkeys. Are they caused by hepatitis B or sv40 in humans?
As for my original carcinogen example of simple benzene, it has been associated with Leukemia when consumed, which means it goes to the bone marrow. Viruses that infect the bone marrow like respiratory syncytial virus have been associated with the disease too. Children with acute lymphoblastic leukemia have often been exposed to RSV in the first nine to 12 months of life. Was it a combination of RSV and benzene exposure? Benzene appears in the waste water of fracking and could be contaminating the well waters of people living near them.
Ovarian cancer HPV18 and CMV herpes viruses.
HPV18
http://www.nature.com/articles/srep08645
The CMV ovarian cancer form would be methylated while the HPV18 form would be demethylated
demethylation
https://www.ncbi.nlm.nih.gov/pubmed/11431104
The carcinogen of ovarian cancer is asbestos or talc powder. The asbestos fibers were found in the ovaries and fallopian tubes in addition to asbestos workers having increased rates of ovarian cancer. The association of talc has not been proven but is suspected.
Liver cancer
HIV and hepatic spindle cell tumors (kidney spindle cells)
https://www.ncbi.nlm.nih.gov/pubmed/8008509
There is not enough evidence to prove that cancers wear the receptors that the viruses used to infect them but there is enough to investigate the possibility. With luck this will prove Co-carcinogenesis and we can prevent most cancer with vaccines. Assuming we figure out how to make vaccines for all of these viruses. One can only hope.
