"The most notable in cancer in 2015 and 2016

 

Viruses linked to cancer

 

  • Most liver cancer comes from Hepatitis B or Hepatitis C.

  • Almost all cervical cancers come from HPV. The CDC (centre for disease, control and prevention) estimates that about 72% of oropharyngeal cancers can come from HPV, although many of these cancers can be linked to tobacco and alcohol use.

  • About 15% of head & neck cancers are from HPV according to K. Tang, B. Alaei-Mahabadi et al. who used The Cancer genome Atlas Data (TCGA) in their report ‘The landscape of viral expression and host gene fusion and adaptation in human cancer.’

  • Burkitt's Lymphoma comes from the common Epstein-Barr virus although Hepatitis C, HIV and malaria have been associated.

  • A February 2013 report evaluating the signifance of infection in breast cancer, concluded that members of the herpesvirus, polyomavirus, papillomavirus, and retrovirus families associate with breast cancer. ('Role of viruses in the development of breast cancer', Kenneth Alibek, Ainur Kakpenova et al.)

  • The cancer genome atlas revealed that 9% of gastric tumours were related to the Epstein-Barr virus.

  • Even in lung cancer, where we know smoking causes cancer, we cannot rule out viruses as a co-factor.

  • We have little hard evidence that viruses are a cause in other cancer types.

 

Cancerdata.com pulls together data on viruses and bacteria. The return of the virus as a cause for cancer or co-factor is identified as "the most exciting thing emerging in 2015 that few people are getting excited about". 

 

1. The success of immunotherapy is the first clue and suggests we might look for the reasons it is successful

 

The first clue about a potential viral cause of cancer emerged in 2014 and 2015 as immunotherapy trials confirmed statistically significant survival benefits that in some cases were durable i.e. long lasting. New immunotherapy treatments are concerned with immune cells called T cells and ensuring cancer cells; or cells that have no long-term future; undergo programmed death, also called apoptosis. Turning T-cells "back on" to attack cancer cells and "ensuring apoptosis" is one concern of immunotherapy treatments today. PD-1 exists on the surface of T cells. Programmed death ligand 1 or PD-L1 is a receptor that exists on the surface of cancer cells. When PD1 binds to PD-L1 ; cancer cells may not undergo programmed death. Immunotherapies have successfully inhibited the PD-L1 molecule, on cancer cells so that it does not bind to PD-

 

1. Firstly, inhibiting PD-L1 has reactivated T-cells so that they attack cancer cells. Because of the success of immunotherapy; common sense suggested we could ask why PD-L1 exists on the surface of cancer cells? (Comment: do we need to 'catch-up" and induce apoptosis all at once? Perhaps a preventative or more paced approach would be better?)

 

2. Secondly, perhaps more importantly, certain viruses do exactly the same things as cancer cells do to evade detection by the immune system.

 

Viruses produce molecules on the surface of our cells to stop T-cells from attacking the cells that host them. For instance Hepatitis B produces HBV surface antigens called vireons. These molecules signal to the immune system that cells are "normal" and should not be attacked by the immune system. In future viral treatments may be a good treatment for cancer.

 

3. A third clue left many years ago is that paclitaxel was once used as an anti-viral.

 

A certain type of chemotherapy called Paclitaxel (Gemzar) is a cornerstone of cancer treatment today, used now as chemotherapy for many solid tumours including lung, breast, prostate, ovarian, bladder and esophageal cancers. Its orginal use as an anti-viral is an important clue in understanding possible causes of cancers. Read on to see the clues that have been left in the last 50 years on the link between viruses and cancer. Some clues have been around all along, whilst in 2015 more recent indications emerged to support the viral theory.

 

Paclitaxel has also been used for prevention and narrowing of coronary stents (restenosis) where it is delivered via the coronary artery and it limits scar tissue growth! (This reminds me of the role of serotonin in the repair of cells). It is worth asking why an anti-viral like Gemzar was so useful in treating cancer. Paclitaxel is originally sourced from yeast that grows on the bark of the yew tree. Read more about it in pancreatic cancer.

 

4. Genes that defend against viruses can sensitise cancers to chemotherapy. “In a report published in Cell on August 27th, 2015, researchers led by Stephen Baylin, M.D., revealed that DNA methyltransferase inhibitors (DNMTis) can trigger an anti-viral immune response that may sensitise cancers to already developed immunotherapies like immune checkpoint therapy. Using the Cancer Genome Atlas data (TCGA), the scientists also showed that patients with certain cancers can be grouped based on their cancer’s expression of genes that defend against viruses. These low or high expression groups may help to predict which patients respond the best to immune checkpoint therapy, and which patients may benefit from co-treatment with DNMTis to help alert the immune system to cancer.” Source:DNA methylation inhibitor triggers anti-viral immune response in cancer, Amy Blum, TCGA website. Boston Biotech also shows that cancer stem cell agents can sensitise cancer cells to chemotherapy (still needs to be verified by larger trials). Other companies think they can induce the expression of PD-L1 on cancer cells (that could make cancer cells more sensitive to immunotherapy).

 

5. Viruses cause genetic mutations by producing proteins that inactivate tumour suppressors.

 

Current thought is that human tumours come from mutations rather than from viruses, however, “causing mutations” is also one of the things that viruses do. To summarise the complex biology - a mutant p53 gene, found in more than 50% of human tumours, can be inherited - but is most often caused by somatic mutations, in other words mutations acquired in a person's lifetime. One of the ways such a p53 mutation can be acquired, is by the HPV virus, in early infection. Viral causes have been rejected for the majority of cancers, but viral treatments offer hope for cures, given cancer cells behave in a similar way to virus cells and given we now have more viral cures, for instance we can now functionally ‘cure’ hepatitis C, which we couldn't do in 2013.

 

Complex biology - sourced and quoted from the UCSF tumour suppressors module.

 

"One of the ways a normal p53 gene restrains tumour formation is by inducing apoptosis (cancer cells destroy themselves), so a mutation is one of the most common ways in which pre-apoptosis regulators are lost. Tumour suppressor genes may be divided into two general groups: promoters and caretakers. Promoters are the traditional tumour suppressors, like p53 and RB. In colon cancer for instance, after a series of mutations, the later progression from late adenomas to malignant carcinomas is associated with the loss of the p53 tumour suppressor (quoted from UCSF tumour suppressors module). Several viral genes are expressed during early HPV infection (E1-E7). Simplifying, the E6 protein inactivates p53 by causing the degradation of the protein. The protein encoded by E7 directly binds to Rb and inactivates it. Thus Rb can be inactivated by loss of the gene (as in retinoblastoma and other tumours), by mutations in genes that control Rb Phosphorylation, or by inactivation of the protein by a viral protein (in this case of HPV). As in genetic loss of Rb, inactivation of the Rb protein leads to the activation of the E2F transcription factor and transcription of the cyclin E gene. Without the safeguards of both p53 and Rb, the cell is strongly driven toward cancer. p53, located on chromosome 17, is the single most common target for genetic alteration in human tumours. More than 50% of human tumours contain mutations in this gene. Thus it is among the most important “brakes” on tumour formation. Homozygous (where both copies of the gene are mutated) loss of the p53 gene is found in virtually every type of cancer, including tumours of the breast, colon, and lung. In most cases, the inactivating mutations affecting both p53 alleles are acquired in somatic cells. And this is why some individuals have a greater chance of developing a malignant tumour by age 50. In some cases, although it is rare, individuals inherit a mutant p53 allele (a blood test can test for the p53 mutation). As with RB1, inheritance of one mutant allele predisposes these individuals to develop malignant (advanced) tumours because only one additional “hit” is needed to inactivate the second, normal, allele. Inactivation of the second p53 allele leads to increased cell proliferation, decreased apoptosis, and tumour development. These individuals have a rare cancer predisposition syndrome called Li-Fraumeni syndrome, and have a 25-fold greater chance of developing a malignant tumour by age 50, compared with the general population"

 

6. 80% of Liver Cancers come from the Hepatitis B or Hepatitis C Virus

 

This supports the viral theory, but only in liver cancer and others described above. In cancer, liver cancer is the second leading cause of deaths world wide, and it is particularly prevalent in Asia. Only about 3% of cases of the Hepatitis B and C Virus lead to liver cancer. However if you do get liver cancer, more than around 80% of the time, it will come from Hepatitis B or C. Viruses have a slow effect on liver cells that then lead to cirrhosis, a damage and repair cycle of tissue and cells, inflammation and ultimately cancer.

 

7. Certain viruses can take a long time to cause cancer. This clue relates to time and points to when a cause for cancer might occur.

 

For patients who are unfortunate enough to develop liver cancer from Hepatitis C, how long do you think it takes from contracting the Hep C virus - on average - to dying from liver cancer?

 

Comments:I thought the answer would be about 3-4 years. Although more than 80% of liver cancers are caused by Hep B or C, the virus itself is contracted an average of 28 years before actual death from liver cancer. This suggests we may wish to look much further back in time, for causality, for instance, by generating national databases of viruses, bacteria and toxins we harbour as teenagers. Could a similar thing be happening with, say Alzheimers, where we contract a virus affecting nerve cells earlier on in life? And could early viral infections be associated with lung disease? Most people who have COPD are at least 40 years old when symptoms begin. And with colorectal cancer, 20% of it may be inherited including ‘common family exposures,’ which may involve exposure to common viruses.

 

8. Viral clearance (and tumour recognition for clearance) may have a relationship to MHC class[1]. Some people infected with Hepatitis B have the immune systems to clear the virus, others don’t and this may relate to why they develop liver cancer. Reference: {1]‘Hepatitis B virus down-regulates expressions of MHC class I molecules on hepatoplastoma cell line. Chen Y1, Cheng M, Tian Z, October 2006.

 

9. Different viruses affect different cells. There are thousands of viruses and they all affect different cells. (As an aside, do different viruses also affect different T cells?) For instance the hepatitis virus affects liver cells and the herpes virus, such as the Epstein-Barr virus affects nerve cells. Taking blood tests to identify all the antibodies we have to viruses earlier on and at different stages of life, might provide useful information in the future when we know more about cancer and it's causes. Because there are so many viruses that could cause cancer; the sheer number of viruses provides a clue suggesting we may have missed a virus, especially if it was latent or hidden when testing; or if we do not yet have the equipment to test tumours for all viruses. Unidentified viruses could also be causes. Viruses may be causing more cancers than we know about. Common, known or unknown viruses may cause mutations in oncogenes or cancer suppressor genes. Alternatively viruses may flare, or lead to cancer-causing bacteria or 'damage and repair' mechanisms that lead to cancer. It is possible that carcinogens (e.g. smoking) may make our organs or tissue more susceptible to viruses, or the food we eat may make us more virus-prone. A fatty liver, for instance, makes us more prone to viruses.

 

9. The success of combination treatments in immunotherapy is a new clue suggesting cancer cells may have viral-like properties

 

Immuno-oncology works by turning the immune system back on, which has been de-activated by cancer. Viruses, like Hepatitis B, produce surface antigens in a similar fashion to evade or de-activate the immune system. (A counterargument is that it is the “effects” of the virus that lead to cancer, such as liver tissue damage in liver cancer, rather than the virus itself.) 

 

It is possible that combination therapies in immuno-oncology are reaching more diverse genotypes of viruses and that may be why combination agents are more successful in cancer too? This is similar to the success of combination treatments in Hepatitis C where combination antiviral enables more diverse genotypes of the Hepatitis C virus to be attacked. Combination therapies have been one of the reasons since 2014 we have been able to functionally cure Hepatitis C. Also in multiple myeloma (antibody blood cancer of the white blood cells) Cancerdata.com understands proteasome inhibitors add another year to survival (now 4.5 yrs median survival). In many cancers combination chemotherapies also achieve higher success rates. Combinations also contribute to the success of Chinese medicine, a medical system much older than our own.

 

10. Recent studies on PD-L1 and HPV in esophageal cancer (negative clue, but just one virus was tested in relation to esophageal cancer).

 

A presentation at ASCO 2015 enquired whether esophageal patients who expressed PD-L1 had higher HPV antibodies. No correlation was found. In esophageal cancer more than 30% of them come from HPV, so the study may refute that the Hepatitis C virus and cancer cells behave in the same way. However this study relates to one virus and only to strains that could be identified. Other viruses or strains could still be implicated.

 

11. The Cancer Genome Atlas (TCGA) work has shown Epstein-Barr virus related gastric tumours made up 9% of gastric tumour types in a study (see colorectal cancer). This subset of tumours did not have many mutations, but PDL1 and PDL2 expression on these tumours was high. This may explain why some patients respond better to some of the anti-PDL1 immunotherapies, despite that the mutational load is low. Recall that certain cancer patients tend to respond better to immunotherapy when they have the expression of the PDL1 molecule on cancer cells and also when mutational load is high.

 

More on HPV

 

On 22 June 2015 Bluebird initiated a partnership with Kite to develop products directed against an HPV protein. Bluebird contributes gene editing whereby it modifies certain genes to enhance T-cell function and Kite contributes its TCR platform (refer immuno-oncology drugs for more on TCR). From the Bluebird website: Human papillomavirus (HPV) is the most common viral infection of the reproductive tract, with two viral strains, HPV type 16 and type 18, believed to cause 70% of cervical cancers and precancerous cervical lesions, as well as other urogenital cancers.[1] There were over 500,000 new cases and about 270,000 deaths attributable to cervical cancer worldwide in 2012. Additionally, HPV infection has become established as an etiologic risk factor for oropharyngeal head and neck cancers. The incidence of HPV-associated oropharyngeal cancers has been increasing for at least the past decade, and recent studies show that about 70 percent of oropharyngeal cancers may be linked to HPV[2],[3]. According to the CDC, there are over 12,000 new cases of oropharyngeal cancers in the US, of which an estimated 7,500 new cases are attributable to HPV-16.4.

 

References for HPV:

 

[1] World Health Organization, Human papillomavirus (HPV) and cervical cancer, Fact sheet N°380, accessed 6/10/15.

[2] Human papillomavirus and rising oropharyngeal cancer incidence in the United States, Journal of Clinical Oncology, 2011: 29(32): 4294-4301.[3] CDC: How Many Cancers Are Linked with HPV Each Year? (http://www.cdc.gov/cancer/hpv/statistics/cases.htm), accessed 6/10/15.)

 

12. Immunotherapy is showing strong signals in early liver cancer and lymphoma trials. Both cancers are associated with viruses. If this isn’t indication enough that viruses may play a larger role in cancer than we think, cancerdata.com finds it notable that the classic immunotherapy results are so outstanding in Hodgkin lymphoma rather than non-Hodgkin lymphoma. Although the cause of both Hodgkin and non-Hodgkin lymphomas is still largely a mystery, we do have clues. For instance Hodgkin lymphoma, which responds better to immunotherapy, has been more frequently associated with a viral cause than non-Hodgkin lymphoma has. Opdivo (one of the classic immunotherapy drugs) also showed a remarkable signal in Hodgkin lymphoma (an 87% response rate) rather than in non-Hodgkin lymphoma (only around a 40% response). Similarly in gastric cancer, patients with Epstein-Barr virus associated tumours, responded better to immunotherapy drugs. Cancerdata.com thinks these responses indicate we could return to a more old-fashioned theory that viruses cause cancer.

 

13. Viruses and bacteria go hand-in hand

 

This is clue because we know that bacteria can also cause cancer, and viruses and bacteria are related. A virus can lower the immune system, which then allows bacteria to thrive. About 27 million people worldwide have chronic obstructive pulmonary disease (COPD) and it is the fourth leading cause of death in the world. Many COPD related deaths are from infections from the bacteria pneumonia. Notably - it is common for a virus to be a trigger. First we get a virus and second, this lowers the immune system enough so that an infection like pneumonia settles in. Other bacteria such as fusobacterium found in colorectal cancers, and Helicobacter pylori could be activated after viral flares.

 

Our bodies may accept bacteria when we don't get enough nicotinic acid

 

There is research that suggests that in certain times in history, for instance when there is famine or when tryptophan is low, our body will actually lower the immune system to accept certain bacteria like tubercolosis (TB), in order to get essential nicotinic acid it needs from tryptophan. Research suggested that in times in history when the body didn't get enough meat, tryptophan levels were too low and our bodies switched off our immune system to TB bacteria, and welcomed it! Are we missing an essential nutrient and does cancer grow or 'enable' bacteria to get it? Do cancer cells harbour bacteria that produce an essential acid? Does the immune system classify the cancer cells harbouring bacteria, as 'self'? If we get the essential nutrient, do we no longer need cancer cells? For more on nicotinic acid refer the chapter on stem cells and also see some interesting observations on this topic below.

 

Bacteria can lower tryptophan

 

In the article 'Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches’ the authors highlight the nicotinamide-and tryptophan-to-NAD pathway (see NAD below) is a “tolerance” link with the immune system, allowing selected symbionts to prosper. Many infections (for example, Toxoplasma gondii, Leishmania donovanii, and Chlamydia) activate this pathway and may stimulate NAD production to the host’s benefit at times, but these infections often consume tryptophan, as it is important for their own growth. More importantly, however, they also produce toxic compounds.

 

Note that if we don’t get enough NADH, too much reactive oxygen species (ROS) may be generated that the body cannot deal with (refer Watson in stem cell section). Put more simply, infections like Leishmania and Chlamydia may increase NAD. However they may simultaneously decrease tryptophan and increase other toxic compounds. The IDO enzyme can stop these bacteria, but unfortunately the IDO enzyme also stops T-cells, so cancer cells might then escape immune surveillance. Refer to stem cells for more and new immunotherapy drugs for detail on IDO inhibitors in the pipeline.

 

Nicotinamide adenine dinucleotide  (NAD)  - it comes in two forms called NAD+ or NADH

 

The body can use either tryptophan (as the de novo or original pathway) OR it can use vitamin B i.e. niacin (the salvage pathway) to convert to an essential fuel called nicotinamide and to the enzyme NAD. NADH is essential for metabolism and development, regulating everything from reproduction to DNA repair and ageing. A shortage constrains brain growth, learning and connectivity.Tryptophan is an amino acid and a precursor for serotonin and other compounds. Vitamin B3 (Nicotinic acid or niacin) is neccessary because the body converts it to an essential fuel called NADH. Despite being a salvage reaction, the body still needs the vitamin B (niacin) pathway since we know that the condition pellagra can arise if we lack vitamin B3 (source: wikipedia on NAD).  Source:'Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches: Co-Evolutionary Relationships with Modern Repercussions?' Adrian C. Williams and Robin I.M. Dunbar et al. 15 Oct 2013. Interesting points from this paper - particularly note that Vitamin B3 protects against UV radiation-induced DNA damage and that NAD strongly absorbs UV light.  In a further step NAD+ is converted to NADP. Normally ATP is the source of the phosphate group, although in bacteria like mycobacterium tubercolosis they use polyphosphate. Organisms like influenza and candida can only get external NAD+ or its precursors from the salvage pathways i.e. from niacin, whereas chlamydia has no pathway to the enzymes NAD and NADP+ and chlamydia must acquire these enzymes from its host. Vitamin B3 heavily protects against UV radiation induced DNA damage (source: Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin, Surjana D, Halliday GM et al.  May 2013 Pubmed). NAD and NADH both strongly absorb UV light, because of the adenine – this is how it is measured.  Nicotanamide is anti-inflammatory and used in some acne treatments. Typically resistance does not develop, but acne returns when use is stopped. Small intestinal overgrowth can cause a deficiency of NAD.

Refer Finding the links for more on Vitamin D and immunotherapy and refer stem cells section for more explanation of NADH.

 

Notes

 

Cancerdata.com notes the 'boom' in the biotechnology industry from curing Hepatitis C

 

The cure for hepatitis C can explain some of the success of the biotechnology index. Gilead’s share price in 2010 was around $20 and it has increased by more than 300% since then to around $100 at the end of 2015. This has represented an increase in the market capitalisation of the company of just over $100bn in the past 5 yrs and has driven outperformance of the biotech index. The market capitalisation of the company at the end of December 2015 was just over $145bn. Sales of Gilead’s lead Hepatitis C drugs Sovaldi and Harvoni were close to $5bn in the 2nd quarter to June 2015 of a total of over $8bn of quarterly sales. Net income for the quarter to June-end 2015 was around $4.5bn. Sales of Zydelig, the new leukemia drug from Gilead are expected to be around $1bn per annum (these forecasts were adjusted downwards in 2016 with set-backs in Zydelig).

 

Large molecules such as antibodies and biologics cannot get into a cell in order to eliminate a virus

 

We need to activate T-cells to get into cells and eliminate viruses. Antibodies are too large to enter cells (small molecules can enter cells.) This suggests part of the cure may be a combination of large and small molecules.

 

Antibody. A large Y-shaped protein on the surface of B-cells; produced by white blood cells. Each tip of the Y contains a structure capable of binding to antigens, such as foreign viruses, bacteria, parasites and toxins. The antigen can be neutralised upon binding. Also called an immunoglobulin. A blood test can reveal which antibodies you have. One might have antibodies to the Epstein-Barr Virus (many people do) for instance, or antibodies to tick-bite fever just as one example of many, indicating that at one time the immune system produced antibodies to attack and neutralise (hopefully) such foreign threats.