Cancer: What We Know Now

Cancer: What We Know Now

by David Archibald

8 August 2018

 

To put the story into context, let’s start with President Nixon declaring war on cancer with the National Cancer Act he signed on December 23, 1971.  The amount of resources applied to cancer research since even exceeds what has been squandered on climate science, but cancer incidence and death rates have remained much the same. This is a result of starting from the wrong paradigm.

 

Figure 1:  Trends in Age-Adjusted Cancer Death Rates by site, Males, US, 1930-2014

 

As Figure 1 shows, apart from cancer by lifestyle choice, cancer death rates have been mostly flat.

The discovery of chemotherapy as a cancer treatment started with a German air raid on the port of Bari, Italy in December, 1943. This set off some of the mustard gas bombs carried as secret cargo by the SS John Harvey. Autopsies of some of the 2,000 people who had died as a result of the air raid showed suppression of cells which divided fast. From that observation it was deduced that mustard gas-like agents might be used to treat cancer. That was followed in the 1960s by the discovery that the bark of some trees contained molecules that had efficacy against cancer cell lines. One of the first of these was taxol from the bark of a Pacific yew tree sampled in Washington State’s Gifford Pinchot National Forest.

Traditional chemotherapy works by causing mitotic arrest. During mitosis, the chromosomes, after having duplicated, condense and attach to spindle fibres that pull one copy of each chromosome to opposite sides of the cell. The spindle fibres are unable to separate due to the chemo and the cells get stuck in a phase of cell division. Cells stopped while they are dividing become unviable and die. The role of these molecules in plants is to stop insects from eating them by stopping cell division in the insect; that is why the molecules are in the bark. Chemo affects all dividing cells which means that it generally useless against a slow-growing cancer like prostate cancer.

In humans, chemotherapy is usually give at a dosage rate just short of what might kill the patient. The danger of low dose chemotherapy is that the cancer might mutate around the drug and become refractory to it. Then the patient has to be switched to another drug if he is to have a chance of surviving. Some patients go from one drug to the next until they run out of options.

In the 1990s there was a brief phase during which targeting receptors over-expressed by cancer cells was popular, mainly the epidermal growth factor receptor (EGFR). Generally drugs targeting EGFR held up disease progression for a few months and then the cancer mutated around the drug. These drugs are still with us and they are hideously expensive. For example Bevacizumab, a monoclonal antibody that targets EGFR, retails at 305,000 euros per kilo – nine times as expensive as gold. Just because it’s expensive doesn’t mean it’s effective: “One study found that the incremental cost effectiveness of second-line treatment with Bevacizumab…. was $162,018 per quality adjusted life year (QALY) gained.” By comparison the platinoid drugs carboplatin and cisplatin are $27,400 per kilo and $31,300 per kilo respectively.

The 1990s also saw a major advance in our understanding of how plants and animals deal with cells that have gone out of control. This is programmed cell death, called apoptosis. Apoptosis starts with a protein called p53 which checks that DNA has been replicated correctly. If it can’t fix the DNA, a signal is sent up to the cell surface to express more death receptors. Half of human cancers have a mutated p53 gene. All cells have death receptors on their external membrane. What binds to them is a protein called Fas ligand. Binding of Fas ligand to the death receptor starts the apoptotic cascade of the caspases. Caspases further down the caspase chain chop up the cellular structures so that the cell’s contents can be carried off in the intercellular fluid. This is more efficient than having dead cells being cleaned up by macrophages.

 

Figure 2: A simplified representation of the apoptotic cascade of the caspases

 

A good overview of how cancers form is Douglas Hanahan and Robert Weinberg’s The Hallmarks of Cancer, published in the journal Cell in 2000. That paper has been referenced over 15,000 times by other research papers. In summary, cells go through six mutations to become cancer cells:

  1. Self-sufficiency in growth signals.
  2. Insensitivity to growth-inhibitory signals.
  3. Evasion of apoptosis.
  4. Limitless reproductive potential.
  5. Sustained angiogenesis.
  6. Tissue invasion and metastasis.

Later that decade a major advance was made in cancer science with the discovery of cancer stem cells, similar to adult stem cells. These make up a minute proportion of a cancer’s mass but contribute most of the cell division. Cancer stem cells are harder to kill than ordinary cancer cells. Their existence explains why some patients appear to go into remission with the disappearance of the whole tumor only to have the cancer reappearing a couple of years later.

A cancer can’t grow to more than about 1 mm in diameter without a dedicated blood supply. Eventually the cancer will mutate to cause blood vessels to growth towards it. This process is called angiogenesis.

The cellular machinery for dealing with mutation was developed a couple of billion years ago during the evolution of the plants. We know that because animals have the same proteins for apoptosis as plants, with a few more developed over the last 660 million years.

 

Figure 3: The development sequence to multicellular animals

 

What keeps this system in homeostasis is a balance between pro-apoptotic and anti-apoptotic proteins. For example there is a molecule called c-FLIP (short for cellular FADD-like IL-1β-converting enzyme-inhibitory protein) produced in the death receptor which stops accidental triggering of the receptor. If that doesn’t work, the next step in the chain is another anti-apoptotic protein called XIAP (X-linked inhibitor of apoptosis protein). There are also pro-apoptotic proteins. About 82 anti- and pro-apoptotic proteins have been identified to date. Mathematical modelling suggests there are more. Proteins involved in the apoptotic cascade have a half-life of about five hours, so guarding against mutation is a significant physiological load. About 90 percent of cancers are immortal due to over-production of anti-apoptotic proteins.

It turns out that we have a cellular mechanism ready to counter the over-production of anti-apoptotic proteins. This was discovered by the husband and wife team of Professor James Morre and Professor Dorothy Morre at Purdue University. Their work is compiled in a book published in 2013 entitled ECTO-NOX Proteins: Growth, Cancer, and Aging. In short, there is a cell surface protein they called cNOX that ordinary cells have which provides the energy for the production of a couple of the anti-apoptotic proteins. In cancer cells, up to 60 percent of the cNOX molecules are replaced by tNOX (the “t” is for tumor) molecules on a signal from the nucleus. It seems that the expression of tNOX on the cell surface is part of the programmed reaction of the cell in encountering irreparable DNA damage.

Nothing binds to cNOX, but a number of plant molecules bind to tNOX and have the effect of inhibiting it. The tNOX molecule has two binding sites and the inhibition effect is higher if both sites are bound simultaneously rather than just one at a time. There is a parallel with vitamin C. Our species doesn’t make its own vitamin C. We rely upon getting enough in the diet. All other mammals, apart from primates and guinea pigs, make their own vitamin C. Presumably there was an evolutionary advantage in losing the ability to make vitamin C. Similarly, the tNOX molecule evolved in the expectation that certain plant molecules would always be in the human diet.

The tNOX molecule is shed into the blood. The Morres realised that if tNOX was detected in a blood sample that meant that there was a cancer somewhere in the body. It turns out that there are many isomers of tNOX, depending upon the organ site. The Morres commercialised a test, based on tNOX, which will detect 25 different types of cancer using 2D electrophoresis. The test can detect cancer up to five years ahead of clinical diagnosis. Here are two Youtube videos on the science of the blood test:

 

There are a couple of good reasons to believe that the human response to cancer evolved to rely upon plant molecules being in the diet to counter the overproduction of anti-apoptotic proteins. Firstly, cancers over-express β-glucuronidase. Glucuronidation is how foreign molecules are cleared from the blood stream, by  attaching a sugar molecule in the liver so they can be excreted by the kidneys. β-glucuronidase reverses this by cleaving off the sugar molecule. In human prostate cancer, the level of β-glucuronidase is 3.6 times higher than in normal tissue.  The fact that cancer cells reverse glucuronidation to release foreign molecules within them means they expect certain plant molecules to arrive in the blood stream. What molecules would they be?

 

Figure 4: Prostate cancer incidence and mortality

 

Secondly, there are vast epidemiological difference in cancer rates due to diet. Japanese migrating to the United States go to the US breast cancer rate, which is six times higher than the Japanese rate, within a generation. The difference is largely due to the higher consumption of legumes in Japan. One of the biggest differences in cancer rates is between the North American prostate cancer rate and the Vietnamese prostate cancer rate, with the former 40 times higher than the latter as Figure 4 above shows.

The incidence of prostate cancer and breast cancer are the same, with currently 11 percent of men in Western countries being diagnosed with it at some point in their lives and five percent dying from it, while 11 percent of women in Western countries are diagnosed with breast cancer at some point in their lives and five percent die from it. It need not be like this. Westerners eat a high proportion of comfort food that lacks the tNOX inhibitor molecules that we evolved to rely upon in our diet. The effect is shown in the following graph of some epidemiological variation in PSA levels:

 

Figure 5: Mean PSA levels by age group and country

 

As figure 5 shows, most Asian countries keep their neoplasias under control through diet and thus don’t suffer the same rate of the progression of disease that Westerners do.

 

Figure 6: Breast cancer incidence by age group and country.

From:  Cancer Biol Med. 2014 Jun; 11(2): 101–115.

 

Figure 6 shows that the breast cancer incidence rate in Australia, a Western country, peaks at six times the Thai rate. It seems that Thai women are getting a lot more anti-cancer molecules in their diet than Australian women. That doesn’t necessarily mean that there is a special dietary component involved. The fact that plants and animals have the same basic apoptotic sequence suggests that all plants have a similar mutagenic load and contain molecules that have an anti-cancer effect. In fact there are plenty in most pantries as shown by the following table of common plants and the molecules they contain that have an anti-cancer effect:

 

These molecules appear to work by binding to receptors on the cell surface as well as in the cell, also most likely on the surface of the mitochondria and possibly within them. As they don’t affect cell division, they don’t have significant side effects at therapeutic doses. They are all subject to a therapeutic window though. For example sulforaphane, from broccoli and some other cruciferous vegetables, is quite effective at killing pancreatic cancer cells as per this result from work done by Professor Falasca’s group at Curtin University:

 

Figure 7: Sulforaphane against the pancreatic cancer cell line HPAF-

II

HPAF-II is an immortal pancreatic cell line used in lab experiments. The term ‘IC50’ stands for the concentration of an inhibitor where the response is reduced by half compared to a control. µM is millionths of a mole per milliltre. A mole of sulforaphane weighs 177.3 grams so a concentration of 8.263 µM of sulforaphane equates to 1.46 millionths of a gram per millitre.  To put that into perspective, to get that concentration in the blood of a 100 kg patient with pancreatic cancer would only require 0.146 grams of sulforaphane – only a minute amount of this completely benign molecule to kill off half of his pancreatic cancer, in theory.

The difficulties come at a number of stages. Sulforaphane is an unstable molecule so the broccoli plant stores it as another molecule, glucoraphanin. The term “gluco” means that there is a sugar molecule involved. When an insect bites into a broccoli leaf, the vacuole containing sulforaphane is ruptured allowing an enzyme called myrosinase to cleave off the sugar molecule, allowing the sulforaphane molecule to get to work in helping repair the leaf. Myrosinase is deactivated by cooking, even by a couple of minutes. The next problem is that sulforaphane has its highest concentration in the seed. As the plant grows the sulforaphane is diluted so that the mature plant has only perhaps one fiftieth of the concentration of the seed.  The seeds are generally about 1 percent sulforaphane so the adult plants have next to nothing. If the broccoli is cooked then that nothing becomes even less.

If dried broccoli sprouts are consumed then about 10 percent of the contained sulforaphane ends up in the bloodstream. Adding myrosinase increases that to 40 percent. Seed extract optimised on sulforaphane yield can increase the concentration to 10 percent at a cost of $400 per kg of product.  Through that route each gram of sulforaphane in the blood costs $10 to get there, which is much cheaper than the next step up of using synthetic sulforaphane at $35,000 per kilo. If a patient took an oral dose of synthetic sulforaphane then 70 percent is likely to make it into the bloodstream, taking the cost to $54 per gram. This is still a bargain compared to most cancer treatments. Sulforphane has another difficulty in that has to be stored at -17°C because of its instability.

Once a drug gets into the bloodstream the body tries to eliminate it from the bloodstream. Sulforaphane has a blood concentration half life of 2 hours so the concentration is falling 30 percent per hour. The problem from that is that particular concentrations need to be maintained to achieve certain effects. For example this paper found that a sulforaphane concentration from 10 µM inhibited cell viability and proliferation of the colon cancer cell line SW620 but that a concentration of 20 µM was necessary to achieve elevated activity of caspase 3, an effector caspase that starts chopping the cell up. So in turn that means that a large dose has to be taken make sure the blood concentration remains above about 20 µM.

This is graphically illustrated by Figure 8:

 

Figure 8: Blood level of sulforaphane on eigth hourly dosing

 

As Figure 8 shows, if you want to maintain a certain blood concentration by the time of the next dose point, then you have to start with a concentration which is six times higher.

There are two ways around this problem. One is have more dose points – the Morres formulated a green tea extract which they recommended be taken six times per day. Patient compliance falls away rapidly beyond three times per day though. Three times a day means eight hours apart, over which time the blood concentration will fall to 10 percent of its peak. Another solution is to take another molecule which will slow the clearance from the body. Piperine from black pepper and grapefruit juice do this.

Even pine needles have shown an anti-cancer effect as shown by the following titles of papers on the subject:

  1. Pine (Pinus morrisonicola Hayata) needle extracts sensitize GBM8901 human glioblastoma cells to temozolomide by downregulating autophagy and O (6)-methylguanine-DNA methyltransferase expression
  2. Selectivity of Pinus sylvestris extract and essential oil to estrogen-insensitive breast cancer cells
  3. Inhibitory effects of α-pinene on hepatoma carcinoma cell proliferation
  4. Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest
  5. Antioxidant, antimutagenic, and antitumor effects of pine needles (Pinus densiflora)

In theory one could make an anticancer concoction by stuffing pine needles into a pressure cooker, adding a bottle of vodka to perform the ethanol extraction and boiling for 20 minutes.  Most of the ethanol would boil off and you would be left a green liquid that would be cheap and likely effective.

There is still a role for chemotherapy, crude as that is. Take the result of this experiment:

 

Figure 9:  Combination therapy of ginger extract and irinocetin on a glioblastoma cell line

 

Irinocetin is a chemo drug from the bark of Camptotheca acuminata. Giving irinocetin to mice with glioblastoma implanted under their skin resulted in an average reduction in tumour growth of 40.2 percent after 60 days. The effect of adding ginger to the diet of the mice reduced tumour growth by 22.7 percent. The combination of the two was far more effective, completely inhibiting tumour growth. How this works is likely that the ginger extract binds to receptors that stop the overproduction of anti-apoptotic proteins. The irinocetin causes mitotic arrest with the result that a signal is sent from the nucleus to the cell surface to express more death receptors. The reduced production of anti-apoptotic proteins, thanks to the ginger extract, allows the death receptors to work and the apoptotic cascade of the caspases is initiated.

In the 1990s the discoverers of taxol, Monroe Wall and Mansukh Wani, wrote, “Undoubtedly, there are other highly active natural products from plant, marine, and fungal sources as yet unknown which, when discovered, will have therapeutic value. Cancer is not one, but several hundred diseases and will require many different types of agents.” On that subject the Professors Morre reappear in our story. The cNOX molecule they discovered comes in one size in all normal cell types at 34 kilodaltons. They found though that the tumour variant, tNOX, comes in specific combinations of size and pH depending upon the organ site of the cancer as shown in Figure 10:

 

Figure 10: tNOX isomers by organ type

 

This is the riddle of the tNOX isomers. Nature does everything for a reason, so why are there so many isomers? If the purpose of the isomers is to act as a receptor binding site, is it to trap different molecules passing in the intercellular fluid? Does this mean that each of the 117 types of cancer will need a particular combination of plant molecules for optimal response? We are at the beginning of that quest. Professor Falasca and his group are poised to break the stalemate in the war on cancer.

 

David Archibald is the author of American Gripen: The Solution to the F-35 Nightmare

 

(See David’s earlier 2016 update here.)