Abstract:
Many researchers dream about taking the approach a cut off food supply to fight cancer. As it can be known, tumors, being rapidly
growing tissues, need more food than healthy cells do. Cutting off the food supply may be a good way to kill the out of control cells.
While logical in theory, this approach has proved challenging in practice, because starvation harms patients too. In particular, it damages
cells called tumor-infiltrating lymphocytes (TILs), that are one of the immune system’s main anti-cancer weapons.
Starve a cancer but not the patient
In paper published by Cancer Cell authors are trying to craft a
diet that weakens tumors, while simultaneously sneaking vital
nutrients to healthy tissues, TILs included. Team of Dr Longo of
the University of Southern California in Los Angeles, first used
starvation as a weapon against cancer in 2012. In experiments
on mice, they employed starvation in parallel with doxorubicin,
a common anticancer drug. This combination resulted in the
animals‘ tumors shrinking by an average of four-fifts, as opposed
to a half if they were dosed with the drug alone.
The question was the researchers may mimic the benefits of
starvation while minimising its problems in humans. The result
is a diet rich in vitamin D, zinc, fatty acids essential to TILs‘
performance, while the diet must be low in the proteins and simple
sugars that tumors make ready use of.
The test of this type of diet efficacy included injection to mice
with breast-cancer cells. For the first two days after the injections
they fed these mice standard rodent chow, composed of 25%
protein, 17% fat and 58% simple sugars and complex vegetable
carbohydrates. This contained 3.75 kilocalories per gram. They
then put ten of the animals onto a transition diet. Besides its special
ingredients consiste of 0.5% protein, 0.5% fat and 99% complex
carbohydrates that woula be of little value to cancer cells.
After experiment the team found that both the rodents which
had been starved and those which had benn fed the special diet
developed tumors which were only two-fifths of the size of those
found in the mice on the ordinary diet. Later run the experiment
again, but with the addition of doxorubicin. The results were
impressive. In combination with special diet, doxorubicin drove
tumors down to a quarter of the size of those found in control mice,
close to the reduction achived in 2012.
To work out what was happning at the cellular level, researchers
collected samples of breast-cancer tissue from the mice in the
re-run experiment and scanned these for TILs. They found that,
while such cells were indeed present in the tumors of mice fed
ordinary chow, there were 70% more of them in the tumors of mice
given doxorubicin alone, 80% more in those mice that were on the
special diet alone and 240% more TILs in mice that had been given
both therapies.
A follow-up experiment revealed at least part of what was goingon.
An enzyme called haeme oxygenase- 1, which helps regulate
immune responses, turned out to be protecting tumors from the
attention of TILs in mice on the normal diet. Dr Longo’s diet
seems to suppress above enzyme’s production in a tumor, and that
encourages TILs to accumulate. Add in the drug, and the tumor
faces a two-pronged assault. Further work by the team suggests
this approach also works on melanoma, an aggressive form of skin
cancer. A siege mentality can pay off. (Longo et al., 2016)
Humans are able to fight cancer with their own immune system
Human bodies are constantly and succesfully fighting off
the development of cells that lead to tumors. When there is a
disruption to this process cancer is free to develop. Researchers
are investigating the ways to ‚switch on‘ our Natural Killer (NK)
cells. These cells exist to detect and then destroy any deviant cells
in human bodies before those cells go on to develop into tumors or before infection spreads. Natural Killer cells are a key part of
the human immune system that locate other cells posing a danger
to health either because they are infected or because they are
becoming a cancer cell.
It is known that abnormal cells sometimes escape the immune
system and develop into a cancer. The researchers identified a
‚protein brake‘ within Natural Killer cells that controls their ability
to destroy their target tumor cells. In their paper published in May
2016 in Nature Immunology, they showed that when the brake was
removed in an experimental model, the NK cells were better able
to protect the body against metastatic melanoma.
Natural Killer cells rely on a growth factor called Interleukin 15 (IL
15) to activate. Research has shown that an inhibitor protein made
inside the NK cells limits the ability of the NK cells to respond to
IL 15 and therefore kill cancer cells. After identifying for the first
time how this protein inhibits NK cell responses, researchers now
hope that a drug can be developed that will improve the NK cells‘
response to this growth factor and help patients fight cancer with
their own immune system.
This is about learning how to activate the NK cells of the individual
patient and boost their immune system to tackle the disease.
Research may lead to new immunotherapies that supercharge the
body’s Natural Killer cell and maintain it in a highly active state
to more efficiently and specifically fight cancer. (Nicholson &
Huntington, 2016).
Bacteria may assist the immune system response against cancer
Researchers have shown that various types of intestinal bacteria
might be factors in both causing and preventing obesity, and in
other conditions and diseases. Now, a UCLA study suggests that it
could also potentially be used to reduce the risk for some types of
cancer. The research, published online April 13 in a peer-reviewed
journal PLOS ONE, offers evidence that anti-inflammatory ‚health
beneficial‘ gut bacteria can slow or stop the development of some
types of cancer.
It is possible to reduce a person’s risk for cancer by analyzing the
levels and types of intestinal bacteria in the organism, and then
prescribing probiotics to replace or bolster the amount of bacteria
with anti-inflammatory properties. It is not invasive and rather easy
to do. Over millions of years, gut bacteria have developed into
both good and bad types: The good ones have anti-inflammatory
properties and the bad ones promote inflammation. The human
body typically contains about 10 trillion bacterial cells, compared
with only 1 trillion human cells.
Schiestl and his colleagues isolated a bacterium called
Lactobacillus johnsonii 456, which is the most abundant of the
beneficial bacteria, and which has some useful applications outside
of medicine. As a Lactobacillus strain, it makes excellent yogurt,
kefir, kombucha and sauerkraut. In the UCLA study the bacterium
reduced gene damage and significantly reduced inflammation,
a critical goal because inflammation plays a key role in many
diseases, including cancer, neurodegenerative disease, arthritis and
lupus, an the aging process.
Previous research led by Schiestl presented the first evidence
of relationship between intestinal microbiota and the onset of
lymphoma, a cancer that originates in the immune system. The
new study explains how this microbiota might delay the onset of
cancer, and suggests that probiotic supplements could help keep
cancer from forming.
For both studies, Schiestl and his team used mice that had
mutations in a gene called ATM, which made them susceptible
to aneurologic disorder called ataxia telangiectasia. The disorder
affects 1 in 100,000 people, is associated with high incidence of
leukemia, lymphomas and other cancers.
In the Cancer Research paper, Schiestl and his team showed that
in the mice with more of the beneficial bacteria, the lymphoma
took significantly longer to for. In the new study, the researchers
analyzed the metabolites, molecules produced by the gut’s natural
metabolic action in the mice’s urine and feces. They find that the
mice that were receiving only the beneficial microbiota produced
metabolites that are known to prevent cancer. Those mice had also
more efficient fat and oxidative metabolism, whic the researchers
believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria,
lymphoma formed only half as quickly as it did in the other mice.
In addition, mice with the good bacteria lived four times longer
and had less DNA damage and inflammation. These findings lend
credence to the notion that manipulating microbial composition
could be used as an effective strategy to prevent or alleviate cancer
susceptibility. Their findings suggest that composition of the gut
microbiota influence and alter central carbon metabolism in a
genotype independent manner. The use of probiotics-containing
supplements would be a potential chemopreventive for normal
humans, while the same type of microbiota would decrease tumor
incidence in cancer susceptible populations.
(Schiestl et al., 2016,
Bullwinkle et al., 2016)
UCLA has a patent pending on the use of Lactobacillus johnsonii
456 as an anti-inflammatory agent.
Microbiome can mean the difference between life and
death in cancer
Development in microbiome sequencing techniques are today
leading to a personalized therapies for a number of diseases. The
trillions of bacteria in our gut are critical for a wide range of key
functions. While many are aware that our microbiota is important
for digestion, it is now known that it also plays a key role in
our immune system. The gut microbiota consists of up to 2,000
different species of bacteria as well as other kinds of microbes,
including parasites and viruses.
Mapping the microbiome is critical to maintaining good health.
Millions of people today regularly consume food-based probiotics
and probiotic supplements without any map of their current
bacteria. People eat yogurt, drink kombucha, and consume other
fermented foods in the hopes of improving their internal flora. It makes more sense to first map each patient’s microbiome to assess
where they are lacking and only then carefully choose a proper
supplement or eat certain bacteria-rich foods.
Microorganisms in the gut can be used to empower the immune
system to fight cancer, as opposed to traditional therapies that
dramatically weaken it. Perhaps the most astonishing aspect of the
microbiota is its control over the immune system. Particular species
of bacteria have been identified for their ability to upregulate the
activity of antigen-presenting cells (APCs). Without properly
functioning APCs, the immune system cannot respond to threats,
whether it be a virus or tumor. When they are doing their job,
APCs are able to bring the threat to the attention of B and T-cells,
which initiate a chain of events to attack and eradicate the threat.
The observation that Bifidobacterium, many strains of which are
found in the gut, are able to increase the activity of APCs, has the
potential to change the way treatment of cancer and other diseases
is approached.
As with all systems of the body, balance is key. In the immune
system, there is a checkpoint that stops the T-cells from overdoing
it. Unfortunately, many cancer cells are able to take advantage
of this mechanism to shut down the T-cell activity before the job
is done. After a decade of research, a therapy was developed to
prevent tumor cells from cheating the system. The therapy has
been shown to improve the activity of T-cells in up to 35% of
patients with melanoma (a form of skin cancer). A study published
in Science reported that combining this checkpoint blockade
therapy with supplements of Bifidobacterium could produce a
much stronger immune response to tumor cells.
The University of Chicago research team found that variations
in intestinal microbiota affected the growth of melanoma in
mice. Mice who received an oral supplement of Bifidobacterium
improved tumor control to the same degree as those who received
the checkpoint blockade therapy, in comparison with the minimal
tumor control exhibited by mice receiving neither.
When mice
were treated with both Bifidobacterium and checkpoint blockade
therapy, tumor outgrowth was almost completely abolished !
This treatment involves no chemotherapy or radiation, instead, it
empowers the natural mechanisms already present in the immune
system using antibody therapy and a commercially available
Bifidobacterium supplement to increase the activity of the APCs.
The Bifidobacterium supplement used in the Science study to treat
melanoma can be purchased for a mere $42 a bottle.
This holds the promise of increasing the efficacy of anti-PD1
checkpoint inhibition immunotherapy, which currently is only
effective for 25-35% of patients for a durable response. There are
reports of greater numbers with combination of a CTLA4-blocker
and anti-PD1 but this is a difficult treatments with very high
probabilities of toxic side effects. If we can increase the durable
response of anti-PD1 therapy to 65% of patients, we will the face
of cancer treatment.
In addition to cancer, it is becoming well known that the bacteria in
your gut have a big effect on the digestion system. Irritable bowel syndrome (IBS), is a disorder of the gut that affects about one out
of ten people in the world. C. diff, a disease named for the bacteria
causing it, is an infection causing a wide variety of potentially lifethreatening
problems in the gut. Since these diseases are associated
with an imbalance of bacteria in the gut microbiota, fecal matter
transplants (FMTs) can treat the condition by reintroducing a healthy
assortment of bacteria to the gut. As with probiotics, sequencing
the microbiome would allow for a more patient-specific therapy
directed at that problem. This same approach could be applied to
the treatment of any number of diseases, completely changing the
way we think about individualized therapy. We must also cover the
human virome (the collection of all viruses resident in our bodies),
some dormant for years. The new approach to the microbiome and
virome will change medicine as we know it. (Sivan & Corrales et
al., 2015)
The link between altered gut microbes and changes in
appetite and eating behaviors
A new study suggests altering the makeup of gut micobes could be
an effective way to adress obesity and related problems. This is the
first study to specifically identify the mechanism by which changes
in patient’s gut microbes influences the likelyhood for developing
obesity and metabolic syndrome, a cluster of conditions that
include high blood pressure, high blood sugar, excess body fat
around the waist and abnormal cholesterol levels.
In studies on mice, researchers at the Yale University School
of Medicine found that acetate, a short-chain fatty acid, is
responsible for modulating the production of insulin in rodents.
They compared the effects of acetate and other short-chain fatty
acids and discovered that the mice with higher levels of acetate
were more likely to consume a high fat diet. The researchers than
infused acetate into a group of rodents to see wheter it would cause
the animals to put on weight. Injected the rodents with acetate
stimulated insulin secretion by the pancreas.Higher level of insulin
increases the storage of fat and prevents the body from releasing it
for energy production.
Next, they injected acetate directly into brains of these rodents.
This caused an increase in insulin production and stimulated the
secretion of gastrin and ghrelin, two hormones that are known
to increase food intake. To identify the link between altered
gut microbes and changes in appetite and eating behaviors, the
researchers transferred fecal matter from group of obese rodents
to helthy rodents. That caused changes in the gut microbes of the
healthy mice, and changes in acetate and insulin levels that could
result in obesity.
Last year, the journal Open Forum Diseases published a case study
of patient treated for C. difficile infection with fecal transplantation.
Transplanting helathy stool, either through capsules or coloscopy,
has more than a 90% success rate for clearing C. difficile infections.
Her BMI rose from 26 to 33 in little over a year after the transplant.
Physicians suspected the fecal transplant was most likely the cause
of her weight gain, thereby showing the bugs in the gut may very
well determine the girth of one’s belly. (Alang & Kelly, 2014)
Block the metabolism of L-glutamine – the tumors
stopped growing
Researchers in the USA have discovered that reducing the amount
of the L-glutamine amino acid in the body can block the growth
of colorectal cancer tumors in mice. The first clinical trials on
humans are due to begin this summer.
L-glutamine is a non-essential amino acid found in eggs, meat,
fish, dairy products, cereals and pulses. It is also found in raw
spinach and parsley, as well as Asian miso. It’s recommended as
a dietary supplement, for reducing intestinal permeability. Recent
research has established that cancerous tumors rely on L-glutamine
to survive and grow.
In this latest study, researchers found that a subset of colorectal
cancer containing a genetic mutation called PIK3CA (a
commonly occurring mutation in cancer cells) were particularly
high consumers of L-glutamine when growing. When Professor
Zhenghe John Wang and his team reduced the amount of
L-glutamine available to these mutant cancer cells growing in
laboratory dishes, the cells died.
This discovery, outlined in the journal Nature Communications,
inspired the scientists to investigate the effects of depriving the cells
of L-glutamine in mice with colorectal cancer tumors. They found
that when mice were given a compound to block the metabolism of
L-glutamine, the tumors stopped growing. This effect was not seen
in tumors that did not contain the PIK3CA mutation.
The findings, which are currently the subject of a patent application,
could lead to the development of a new drug to suppress tumor
growth. The first clinical trials of an L-glutamine inhibitor in
human patients with advanced stage colorectal cancer will begin
this summer. (Yujun Hao et al., 2016)
The parasite secretes direct the immune system to attack
tumors
Research on the parasite toxoplasma gondii (T. gondii), commonly
found in cat feces, reweals how nasty and widespread it is. It’s
linked to the rage disorder, might boost one’s risk of schizophrenia
and other mental disorders. In an odd and probably fatal twist
makes the mice it infects no longer fears cats.
New research out of Dartmouth’s Geisel School of Medicine
suggests that, at least in mice, it has a major upside: The parasite
secretes specific protein that directs its immune system to attack
ovarian tumors, researchers report in the journal PLOS Genetics.
They built upon previous research to produce a vaccine that’s a
safe strain of T. gondii, one that could cure mice of multiple types
of solid tumors, not just ovarian.
Ovarian cancer usually isn’t detected until it has metastasized (it
has spread to other tissues and organs). As a result, it accounts for
the fifth-most cancer deaths among women, claiming more than
14,000 lives a year, per the American Cancer Society. Researchers
note that clinical trials are already underway exploring the use of
the bacterium Listeria monocytogenes to break the body’s immune
tolerance of pancreatic tumors and essentially whip the immune
system in the attack mode. T. gondii could work in a strikingly
similarly way. What works in mice doesn’t always in humans,
there is a hope to develop therapies that attack the most aggressive
tumors. The Holy Grail of the ovarian cancer may be near. (Fox
et al., 2016)
Kamikaze Bacteria Attack Deep Tumors:
In mice, microbes released anticancer toxin that, with chemotherapy,
shrank tumors. Bacteria have been engineered to manufacture
anti-cancer drugs and self-destruct to spill this cargo deep inside
tumors. In combination with chemotherapy, tha approach shrank a
tumor in a mouse model for liver cancer more than chemotherapy
alone.
To create the cancer therapy, University of California, San Diego
researchers turned to Salmonella as this bacterium likes to colonise
tumors as a way of hiding from the body’s immune system. The
bacterium was engineered to produce the toxin haemolysin, along
with a chemokine to call in the host’s own defences. A ‘kill switch’
was also design into them that would cause the cells to break open
when flipped.
When tested in a mouse model of liver cancer, the bacteria did
not perform better than chemotherapy alone, but in combination
there was a significant effect. For the combined therapy the
researchers observed decreases in tumor size and 50% increase
in life expectancy in mice with metastatic cancer. Think of the
bacteria as an army that enters behind enemy lines, to the interior
of the tumor, which is where chemotherapy finds it hard to reach.
The group previously reported that orally delivered engineered
Escherichia coli colonise liver tumor tissue but not healthy organs.
The simultaneous self-destruction of the bacteria is under the
control of a small signaling molecule, AHL, which flows in and
out of the cells. Its introduction is stimulated by the presence of
AHL so as the bacterial colony grows levels of the molecule rise.
Once the concentration of AHL passes the threshold, a protein
is produced that obliterates the bacteria’s cell wall releasing its
deadly cargo.
Once the density of Salmonella in the tumor reaches a few thousand
bacterial cells, the self-destruction switch is tripped, releasing
more anti-cancer drugs and killing off 90% of the bacteria. The
10% of the bacteria that survive regrow the population. This cycle
of growth, self-destruction and drug release continues.
The bacteria lose their ability to deliver drugs after about 18 days,
but oral administration means it is easy to take another dose.
Researchers are modifying bacteria so that they kill any remaining
bacteria from a previous dose, in addition to cancer cells, so that
they wipe the slate clean.
An advantage with this approach is that the bacteria synchronously
lyse and so their population shrinks. That is a safety mechanism.
This restricts the bacterial population to a defined size, which
minimizes the risk of an adverse systemic inflammatory response
in a patient. This changes our thinking about how to engineer bacteria. It is also a first and more combinations of potent
therapeutics can be now tested. (Omar Din et al., 2016)
References:
- Fox BA, Sanders KL, Rommereim LM, Guevara RB, Bzik DJ (2016) Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls
the Development of Antitumor Immunity. PLoS Genet 12(7): e1006189. doi:10.1371/journal.pgen.1006189
- Longo W. at al., (2016) ...Cancer Cell, Jul 16th 2016
- Nicholson S. and Huntington N. (2016) CIS is a potent checkpoint in NK cell-mediated tumor immunity. DOI: 10.1038/ni.3470
- Omar Din M et al., (2016) Nature, DOI: 10.1038/nature 18930
- Bullwinkle EM. et al., (2016) Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling. Cancer Letters (2016).DOI: 10.1016/j.canlet.2016.06.010
- Schiestl R., Maier I., Fornace A., Cheema A. (2016) ...PLOS ONE,
- Sivan A., Corales L. et al., (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350.6264: 1084-089
- Alang N. & Kelly CR. (2014) Weight Gain After Fecal Microbiota Transplantation. Open Forum Infectious Diseases, 28 November 2014
- Yujun Hao, et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nature Communications 7: 11971,doi:10.1038/ncomms11971
- Zhenghe JW (2016) www.nature.com/2016/160620/
ncmms11971/full/ncomms11971.html
- Dartmouth’s Geisel School of Medicine (2016), PLOS Genetics
- Schiestl RH, et al., (2016) Chemopreventive Metabolites Are Correlated with a Change in Intestinal Microbiota Measured in A-T Mice and Decreased Carcinogenesis. PLOS ONE, April 13, 2016. http://dx.doi.org/10.1371/journal.pone.0151190.
