ISSN:2476-2377

Review Article International Journal of Cancer Research & Therapy

Winning the War on Cancer
Robert Skopec*

*
Corresponding author
Robert Skopec, Dubnik, Slovakia, researcher-analyst, E-mail: zxcbnvm7@
Dubnik Slovakia, Analyst-Researcher gmail.com

Submitted: 29 Apr 2018; Accepted: 07 May 2018; Published: 25 May 2018

Abstract
A new study has uncovered how brain injury can be worsened by bacteria in the gut. The gut-brain connection is
one of the more fascinating new areas of medical research. This intriguing two-way axis has been found to have
numerous unexpected effects. On one hand some studies have demonstrated how magnetic brain stimulation can
alter person’s gut microbiome while other studies have shown how gut bacteria could potentially play a role in
the onset of PTSD (post traumatic stress syndrome) and Alzheimer’s. Studies in patients and subsequent mouse
research really drive home that our gut microbiomes modulate both systemic and anti-tumor immunity, said Jennifer
Wargo, a surgical oncologist and geneticist at the University of Texas MD Anderson Cancer Center. She is planning
clinical trials to see if fecal transplant in cancer patients could improve immunotherapy success rates. The main
conclusion from this is: You can change your microbiome.

Keywords: Brain injury, bacteria, the gut-brain connection, gut The study helps explain why patients suffering from TBI have been
microbiome, two-way axis, blood poisoning, microbial priming, two and half times more likely to die from digestive problems than a
checkpoint inhibitor, the Warburg effect, glucose, glycolysis. person not afflicted by brain injury. The mechanism that is causing
this strange interaction is yet unknown, but this is strong research
Brain injury can be worsened by bacteria in the gut affirming the complexity of above two-way connection between
A new study from the University of Maryland School of Medicine the gut and the brain [1].
has revealed another strange gut-brain connection, this time between
traumatic brain injury (TBI) and intestinal damage. Researchers Gut bacteria make or break your chances of cancer treatment
have previously identified an odd connection between TBI and New, potent cancer therapies can act like daggers pressed into
alterations in person’s gastrointestinal tract, but this is the first hindquarters of the immune system, prodding it to lunge at any
study to understand this interaction in detail and reveal the two-way cancerous cells in the body. When the drugs work, the immune
nature of the process. system tramples tumors into oblivion. But they not always work
– in fact, cancer drugs can fail 60 to 70 percent of the time. The
The study looked at mice that were subjected to TBI, and discovered drugs might not give the immune system a sharp enough sticking
that following the brain trauma, the animal’s colon became more in every patient. But according to a pair of new studies, it may not
permeable. This means that bacteria can more easily move to other be the immune system that needs a swift kick – it may be the gut.
areas in the body, resulting in potentially fatal scenarios such as
blood poisoning. Some intestinal-dwelling bacteria appear to corral and train immune
cells to fight off cancer cells – prior to any spurring from cancer
The team also looked at how irregularities in the gut could affect immunotherapies. Without such microbial priming, the drugs may
inflammation in the brain after TBI. In this instance, after infecting only offer a futile prod. In both studies, published in Science,
TBI-inflicted mice with negative gut bacteria, the animal’s brain researchers found that the cancer patients who saw no benefit
inflammation was seen to worsen. This fascinating result suggests from the drugs (non-responders) were the ones who lacked certain
that the harmful effects of TBI can be directly influenced by gut beneficial gut bugs, particularly after taking antibiotics. Cancer
dysfunction. patients who did respond to the drugs had bacteria that could prompt
the immune system to release chemicals that get cancer-killing
These results indicate strong two-way interactions between the immune cells – T cells – to chomp at the bit.
brain and the gut that may help explain the increased incidence of
systemic infections after brain trauma and allow new treatments When the researchers transferred the gut microbes from their human
approaches, says researcher Alan Faden. cancer patients into germ-free mice with cancer, the rodents mirrored
the patients fates. That is, mice that got gut microbes from non-

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responding humans also did not respond to immunotherapies. But, bacteria may spure the immune system to fight cancer and if there
that got microbes from responders responded. When researchers are side-effects or potential dangers of manipulating the microbiomes
swapped responder gut microbes into non-responding mice, the of cancer patients.
mice converted and fought back the cancer.
These findings highlight the therapeutic potential of modulating
Custom cancer vaccines safely fight and kill tumors in early human the gut microbiome in patients receiving checkpoint blocade
trials. In Dr. Vargo’s study and in other – led by immunologist immunotherapy, and they varrant prompt evaluation in cancer
Laurence Zitvogel of the Gustave Roussy Cancer Campus in Villejuif, patients through clinical trials [2,3].
France – researchers focused on a type of checkpoint inhibitor cancer
treatment called PD-1 inhibitors. Generally, PD-1 is a protein on A new way to shut down cancer cell’s ability to consume glucose
the surface of the T cells that-in non-cancerous scenarious – acts as Joaquin Espinoza, PhD, Mathew Galbraith, PhD, and university of
a checkpoint to guard against over-zealous immune responses and Colorado Cancer Center colleagues demonstrate link between gene
auto-immune diseases. PD-1 does this by latching onto proteins on CDK8 and the ability of cancer to uptake and metabolize glucose.
healthy cells, namely PD-L1, which basically signals to the T cell Cancer cells consume exorbitant amounts of glucose, a key source
to stand down and not attack the healthy cell. of energy, and shutting down this glucose consumption has long
been considered a logical therapeutic strategy.
Crafty cancer cells often don PD-L1, though, allowing them to
escape a T cell blitz. That’s where the PD-1 inhibitors come in. If Good pharmacological targets to stop cancer’s ability to uptake and
the drugs get in the way of PD-1 binding to PD-L1 on cancer cells, metabolize glucose are missing. In a new study published in Cell
they can help unleash the wrath of T cells on those tumors. But, as Reports, a team of University of Colorado Cancer Center researchers,
mentioned, PD-1 inhibitor therapies often don’t work. led by M. Galbraith and J. Espinosa finally identifies a way to restrict
the ability of cancer to use glucose for energy.
Prior to the new study, Zitvogel and colleagues noticed that
recent mouse studies were showing that gut microbes play a role Over-expression of the gene CDK8 is linked to the development
in regulating immune responses to cancers. They hypothesized, of many cancers including colorectal cancer, melanoma, and
the bacteria-killing antibiotics could squash the effects of PD-1 breast cancer, where it regulates pathways that drive the growth
inhibitors. To see of that held up, they simply looked at the outcomes and survival of cancer cells. Altough a number of drugs aimed at
of 249 patients with either lung, kidney, or bladder cancer, some of blocking CDK8 activity are currently being developed, it is not yet
whom received antibiotics around the time of their PD-1 inhibitor clear how effective they are at treating various cancers. Galbraith
treatments. The researchers found a clear link between antibiotic and Espinoza have been working to better understand the role of
use and immunotherapy failures. Specifically, the 69 patients taking CDK8 in canecr biology in the hopes of aiding the introduction of
antibiotics had shorter survival times and periods without their CDK8-based therapies as cancer treatments [4].
cancer progressing compared with patients with the same cancers
and similar health factors. Their recent study, which was funded in part by the Cancer League
of Colorado demonstrates that CDK8 plays a critical role in allowing
Next, the researchers examined the communities of microbes in cancer cells to use glucose as an energy source. The finding takes
the poop of 100 responding and non-responding cancer patients. place against the backdrop of the tissue conditions in which tumors
They found big differences in the abundance of certain types of grow, as cancer cells rapidly multiplay, their growth often outsrips
bacteria. Specifically, those who responded to PD-1 inhibitors their body supply, leading to depletion of oxygen (i. e. hypoxia)
were more likely to carry Akkermansia muciniphila, an intestinal and other nutrients such as glucose. In 2013, the group published
bacterium hypothesized to have anti-inflammatory effects. In mouse paper showing that CDK8 is important for activation of many genes
experiments, A. muciniphila spurred immune cells to release a switched on in hypoxic conditions. During adaptation to these
chemical signal called IL-2, which is known to regulate T-cells and conditions, cancer cells must alter their metabolism to consume
prime them to attack. Likevise, treatments of A. muciniphila could more glucose through a process of glycolysis. In fact, many cancer
convert non-responding gut microbes into responding microbes in cells have permanent increases in glycolysis, maintained even in
mice with cancer. conditions of plentiful oxygen, a phenomenon known as the Warburg
effect, which was described as far back as 1924. Consequently,
Wargo’s study had similar findings. In their work with 112 skin many cancers are heavily dependent on glucose metabolism for
cancer patients undergoing PD-1 inhibitor treatments, they, too, their growth and survival. This is true to the point that doctors use
found that patient’s gut mocrobiomes is linked with the success or glucose isotopes and PET scans to pinpoint the exact location of
failure of their immunotherapy. Though they didn’t pick uout A. a tumor and its metastases within human body – where there are
muciniphila specifically, they noted that responders tended to have abnormally high levels of glucose being used, chances are there is
more diverse communities and more of certain types of bacteria. a cancerous growth.
When they transferred the patients’ gut microbiomes into germ-
free mice with cancer, the mice met the same fate as their human When Galbraith used a sophisticated chemical genetics approach to
microbe donors. The researchers also found evidence of beneficial specifically switch off CDK8 activity in colorectal cancer cells, he
microbes priming T cells. saw that the cells failed to activate glycolysis genes and took up less
glucose. He confirmed this in experiments showing that blocking
Together, the studies suggest a big role for gut microbes in CDK8 activity leads to a lower rate of glucose use.
determining the cancer-killing potential of immunotherapies. But
there are still plenty of questions, namely how exactly, certain Because of this role of CDK8 in glycolysis, he reasoned that the

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cells with impaired CDK8 activity should be more susceptible to The best diet according to Harvard researchers
drugs tha block glycolysis. Sure enough, treating cancer cells with If you want to lose weight, what’s on your plate is often more
drugs that block both CDK8 and glycolysis slowed their growth important than the minutes you spend in the gym. And if you want
more effectively than either approach alone. to see the most change, a study from Harvard says that you should
be cutting carbohydrates (carb), not only fat.
These are very exciting discoveries. The Warburg effect and
consequent addiction to glucose is a hallmark of cancerous tissues, For the study, published in journal PloS One, researchers from
something that distinguishes cancer cell from most normal tissues. Harvard and Brigham and Women’s Hospital reviewed 53
Therefore, combining drugs that block CDK8 activity with those randomized trials of over 68,000 patients who had been assigned
that block glycolysis may enable specific targeting of cancer cells to either low-fat or low-carb diets. They found that low-carb diets
without harmful effects on normal cells [5]. were consistently better at helping patients lose weight than low-fat
diets. The participants on the low-carb diets lost 2.5 pounds more
Relationship between sugar and cancer than those on low-fat diets, with an average weight loss among all
A nine-year joint research project conducted by VIB, KU Leuven groups at about 6 pounds.
and VUB has led to a crucial breakthrough in cancer research.
Researchers have clarified how the Warburg effect, a phenomenon Another study on the weight-loss benefits of a low-carb diet adds
in which cancer cells rapidly brake down sugars, stimulates tumor further evidence that if you want to lose weight, ditching bread –
growth. This discovery provides evidence for a positive correlation not olive oil – can help you see success. Another recent study also
between sugar and cancer, which may have far-reaching impacts on showed that dieters who ate fewer than 40 grams of carbohydrates
tailor-made diets for cancer patients. The research has been published per day lost about 8 pounds more than dieters who were put on a
in the leading academic journal Nature Communications. low-fat diet.

This project was started in 2008 under the leadership of Johan Several other studies have shown that high-carb diets may be the
Thevelein (VIB-KU Leuven), Wim Versees (VIB-VUB) and Veerle real heart-disease culprit, not only saturated fat [7].
Jansens (KU Leuven).
All in all, this new review is a good reminder that if you want to
Its main focus was the Warburg effect, or the observation that tumors lose weight, you should choose a diet in healthy fats, lean proteins,
convert significantly higher amounts of sugar into lactate, compared and fresh produce. Of course, not all fats are created equal – you
to healthy tissues. As one of the most prominent features of cancer must find out which healthy fats are recommended by science to be
cells, this phenomenon has been extensively studied and even used to incorporating into your diet [8].
detect brain tumors, among other applications. But thus far, it has been
unclear whether the effect is merely a symptom of cancer, or a cause. Our cells are coated with sugar, and when it comes to cancer, that’s
anything but sweet. In a recent talk at TEDx Stanford, chemical
While earlier research into cancer cell metabolism focused on Carolyn Bertozzi explained why. She studies sialic acid, a sugar
mapping out metabolic peculiarities, this study clarifies the link that seems to deceive the immune system, allowing cancer cells
between metabolic deviation and oncogenic potency in cancerous to evade the body’s defenses. This work focuses on the complex,
cells. sugary structures surrounding human cells. That foliage-like coating,
it turns out, can tell us a lot of our body – it even reveals a patient’s
Their research reveals how hyperactive sugar consumption of blood type. Sugar and carbohydrates are a dangerous supporters of
cancerous cells lead to a vicious cycle of continued stimulation different types of cancer.
of cancer development and growth. Thus, it is able to explain the
correlation between the strength of the Warburg effect and tumor Sugar, carbs and cancer links
aggressiveness. This link between cancer and sugar has sweeping In August of 2016, the New England Journal of Medicine published a
consequences. striking report on cancer and body fat: Thirteen separate cancers can
now be linked to being overweight or obese, among them a number
Yeast as a model organism of the most common and deadly cancers of all - colon, thyroid,
Yeast cell research was essential to the discovery, as these cells ovarian, uterine, pancreatic and (in postmenopausal women) breast
contain the same Ras proteins commonly found in tumor cells, which cancer. In November 2017 a report from the Centers for Disease
cause cancer in mutated form. Using yeast as a model organism, the Control and Prevention added more detail: Approximately 631,000
research team examined the connection between Ras activity and Americans were diagnosed with a body fat-related cancer in 2014,
the highly active sugar metabolism in yeast. accounting for 40 percent of all cancers diagnosed that year [9].

Researchers observed in yeast that sugar degradation is linked Increasingly, it seems not only that we are losing the war on cancer,
via the intermediate fructose 1,6-bisphosphate to the activation of but that we are losing it to what we eat and drink. It is a warning
Ras proteins, which stimulate the multiplication of both yeast and sign that something about what or how we eat is intimately linked
cancer cells. It is striking that this mechanism has been conserved to cancer.
throughout the long evolution of yeast cell to human.
Lewis Cantley, the director of the Cancer Center at Weil Cornell
However, the findings are not sufficient to identify the primary cause Medicine, has been at the forefront of the cancer metabolism revival.
of the Warburg effect. Further research is needed to find out whether His best explanation for the obesity-cancer connection is that both
this primary cause is also conserved in yeast cells [6]. conditions are also linked to elevated levels of the hormone insulin.

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His research has revealed how insulin drives cells to grow and take References
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This is not say that all cancers are caused by too much insulin or
that we should never eat sugar again. Michael Pollak, a metabolism
researcher and director of cancer prevention at McGill University
in Canada, says that the best approach to sugar is think of it like a
spice – something to occasionally sprinkle on foods, as opposed to
an ingredient in nearly every meal and too many drinks.

Nutrition is an inherently messy science. But recent advances in

cancer metabolism research are sending as an increasingly clear
message about our diet. Winning the war on cancer may depend
upon whether we’re ready to hear it [10].

Acknowledgement
The author gratefully acknowledge the assistance of Dr.Marta
Ballova, Ing. Konrad Balla, Livuska Ballova, and Ing. Jozef Balla.

Copyright: ©2018 Robert Skopec. This is an open-access article

distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited.

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