Treating aggressive colon tumor with immunotherapy

Immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind of therapy. Given this observation, researchers hypothesized that this kind of tumour was simply invisible to the immune system.

A team headed by ICREA researcher Eduard Batlle, at the Institute for Research in Biomedicine (IRB Barcelona), explains that the hormone TGF-beta is responsible for the "blindness" of the immune system to colon cancer cells. The few clinical immunotherapy trials done in patients with the most common subtype of colon cancer were not giving good results.

By inhibiting the activity of TGF-beta, the cells of the immune system infiltrate and recognise the tumour, fight the cancer, and even stop colon tumours from metastasizing to the liver and lung in a preclinical mouse model that mimics the human disease. In addition, and more importantly, the researchers demonstrated that the combination of a TGF-beta inhibitor with available immunotherapies boost the anti-tumour effect, allowing the immune system to efficiently eliminate already established metastases that would otherwise kill the individual in a question of weeks.

Scientist Daniele Tauriello, postdoctoral fellow and first author of the article, induced four of the most common mutations present in advanced human colon tumours in mice. After confirming the similarity of the mouse tumours with those in humans, they built a biobank of tumour organoids3-D mini-tumours and grafted them in a controlled manner in immunocompetent mice.

For studies of the immune system, the tumour has to be of mouse origin. Otherwise, the animal would reject it.This animal model which mimics the main features of metastatic colon cancer in humans, allowed the researchers to examine how cancer cells evade the immune system. Around 40 to 50 percent of colon cancer patients relapse in the form of metastasis, with the tumours reproducing mainly in the liver and lung.

Once advanced stage colon cancer is diagnosed, oncologists do not have access to efficient treatments to cure the patient. This study paves the way for the development of the first immunotherapy treatment for patients with metastatic colon cancer and for those patients with poor prognosis but who have not yet developed metastasis. Oncologists and pharmaceutical companies will soon start clinical assays that combine TGF-beta inhibitors, which are already in clinical use, with immunotherapies.

The researchers are convinced that many colon cancer patients will benefit from this therapeutic strategy. In the same issue of Nature, another study addresses the lack of response of bladder cancer patients to immunotherapy.  It appears that many types of tumour use the same strategy-increasing the expression of TGF-beta in the environment to evade the immune system. Patients with these tumours may also benefit from immunotherapies based on the inhibition of this hormone.
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Roles of bacteria in colon cancer

Patients with an inherited form of colon cancer harbor two bacterial species that lead to development of the disease, and the same species have been found in people who develop a sporadic form of colon cancer, a study led by a Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy research team finds.

A second study by the same researchers shows a possible mechanism behind how one of these species spurs a specific type of immune response, promoting-instead of inhibiting the formation of malignant tumors. Together, these findings could lead to new ways to more effectively screen for and ultimately prevent colon cancer.

The Science findings describe a process in which these bacteria invade the protective mucus layer of the colon and collude to create a microenvironment-complete with nutrients and everything the bacteria need to survive that induces chronic inflammation and subsequent DNA damage that supports tumor formation.

These findings suggest a change in the standard of care for people who carry both types of bacteria. "More frequent colon cancer screening than the currently recommended once every 10 years should be considered," says Drew Pardoll, M.D., Ph.D., director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Ultimately, once better understood, administering drugs or vaccines to prevent colonization of the bacteria in the colon, and potentially even probiotics to chase the bugs from the colon, are preventive measures that could be explored to interrupt the cancer-promoting process.

These new findings shows that particular strains of bacteria can invade the colon mucus in some patients who get colon cancer but who have no inherited predisposition for the disease. Unlike most bacteria, which do not make it past the colon's protective mucus layer, these communities of bacteria that invade the mucus form a sticky biofilm right next to the colon epithelial cells that line the colon, where colon cancer usually originates.

About 5 percent of colon cancers are caused by a hereditary syndrome called familial adenomatous polyposis (FAP), in which an inherited mutation launches a series of genetic changes that develop over time and eventually prompt the epithelial cells to turn malignant. However, it was unclear whether ETBF or other bacteria played a role in the progression to colon cancer in FAP patients.

To investigate the relationship between the bacteria-caused biofilms and cancer formation, researchers examined colon tissue removed from six FAP patients. Tests showed patchy sections of biofilms distributed along the colon's length in about 70 percent of the patients. The researchers used gene probes to identify the particular bacterial species and found that the biofilms consisted mainly of two types, Bacteroides fragilis and Escherichia coli, a surprising finding since the colon contains at least 500 different types of bacteria.

Tests on 25 additional colon samples from FAP patients showed that the B. fragilis strain was a subtype, called ETBF, which makes a toxin that triggers certain oncogenic, or cancer-promoting, pathways in colon epithelial cells and causes colon inflammation. The E. coli strain produced a substance called colibactin (synthesized by a set of genes in the bacterial genome called the PKS island), which causes DNA mutations.

FAP is a devastating disease that ultimately results in surgical removal of the colon, a Currently, using colonoscopy to monitor for the formation of precancerous tumors, called polyps, is the standard of care. Using a mouse model of colon cancer, the researchers found that animals whose colons were colonized with just one of these species developed few or no tumors. However, when their colons were colonized with both species simultaneously, they developed many tumors, suggesting a synergy between the two types of bacteria.

An earlier study suggested a unique type of immune response producing an inflammatory protein called IL-17-was key to ETBF-induced tumor formation. In order to prove the importance of IL-17 in the cancer-promoting effects of the bacterial combination, they used a mouse model in which the IL-17 gene was genetically deleted so it could not make IL-17, and colonized the mice with both ETBF and PKS+E. coli. Unlike animals that readily made IL-17, the genetically altered mice didn't form colon tumors, confirming the importance of this protein in bacterial-driven colon cancer.

However, in addition to IL-17, the studies showed that ETBF digested the mucus layer, enabling the PKS+ E. coli to adhere in larger numbers to the colon mucosa where together the bacteria induced increased DNA damage, a step preceding the gene mutations that underlie colon tumor formation. The complementary findings in Cell Host & Microbe demonstrate how ETBF's toxin prompts colon cancer to develop. Using a different mouse model of colon cancer, the researchers colonized the animals' colons with ETBF and then performed a series of tests to monitor the resulting cellular and molecular changes.

Their results revealed that ETBF's toxin spurs a cascade of events that promote colon inflammation that feeds back to act on the colon epithelial cells. First, the toxin triggers colon immune cells to produce IL-17. This inflammatory molecule then acts directly on the colon epithelial cells to trigger activation of a protein complex involved in promoting further inflammation, known as NFkappaB. NFkappaB in turn induces the colon epithelial cells to produce several signaling molecules that recruit more immune cells, called myeloid cells, to the colon.

These immune cells are involved in the inflammatory response and are known to support tumor growth. This process culminates in tumors forming in the colon. Additional experiments showed that a protein known as STAT3, which was previously shown to play a role in regulating cancer and inflammatory genes, is also necessary for tumor formation.
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Links between high cholesterol diet and colon cancer

New UCLA research could help explain the link between a high-cholesterol diet and an elevated risk for colon cancer. In a study of mice, scientists from the David Geffen School of Medicine at UCLA discovered that boosting the animals' cholesterol levels spurred intestinal stem cells to divide more quickly, enabling tumors to form 100 times faster. The study identifies a molecular pathway that could serve as a new drug target for colon cancer treatment.

Cholesterol influences the growth of stem cells in the intestines, which in turn accelerates the rate of tumor formation. The connection between dietary cholesterol and colon cancer is well established. The scientists increased cholesterol in the intestinal stem cells in some of the mice by introducing more of the substance into their diets.

In others, the researchers altered a gene that regulates phospholipids, the primary type of fat in cell membranes, which spurred the cells into producing more cholesterol on their own. The stem cells ' ability to multiply increased in both groups.

As the animals' cholesterol levels rose, their cells divided more rapidly, causing the tissue lining their guts to expand and their intestines to lengthen. These changes significantly sped up the rate of tumor formation in their colons.
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Obesity linked to different cancers

There is a link between obesity and different cancers, being obese or overweight was associated with cancer.
Some of the cancers linked with obesity include: brain cancer; multiple myeloma; cancer of the esophagus; postmenopausal breast cancer; cancers of the thyroid, gallbladder, stomach, liver, pancreas, kidney, ovaries, uterus and colon.

Of all cancers, 55 percent in women and 24 percent in men were associated with overweight and obesity. Blacks and whites had higher rates of weight-related cancer than other racial or ethnic groups. Black men and American Indian/Alaska Native men had higher rates of cancer than white men.

Except for colon cancer, cancers tied to overweight and obesity increased among those younger than 75 years.
Some other risk factors are smoking of cigarettes, drinking of alcohol, genetics,
sedentary lifestyle and poor nutrition.

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Causes and prevention of colon cancer

Colon cancer occurs in the large intestine or in the rectum, it develops slowly. An abnormal growth known as a polyp develops on the inner lining of the large intestine or rectum before the cancer growth.

Familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

 CtBP drives the actions of what are known ascancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy. CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth.

CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell's DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

HIPP acted as a chemical to prevent polyp formation, thereby reducing the risk of colon cancer. Anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis to control and cure colon cancer.
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Grape seed may prevent colon cancer

The combination of resveratrol and grape seed extract is very effective in preventing and treating colon cancer.

Cancer stem cells are capable of self-renewal, cellular differentiation and maintain their stem cell-like characteristics even after invasion and metastasis.

When taken separately in low doses, resveratrol and grape seed extract are not effective against cancer stem-cell, but effective in suppressing cancer when they were combined.

The combination of grape seed and resveratrol can prevent the recurrence of colon cancer in survivors.
When tested on mice, it suppressed tumours in mice fed with the compound.

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Vigorous exercise increases health risks

Vigorous exercise for a long period of time can change the composition of gut bacteria.

The research looked at soldiers taking part in an intensive training programme and found that pro-longed exercise caused the protective barrier in their guts to become permeable and triggered leaky gut syndrome.

Gut health and overall health are linked, intense physiological stress could raise the risks of many types of illnesses.

 Poor gut health is linked to conditions ranging from irritable bowel syndrome, diabetes, high blood pressure, depression, obesity, childhood asthma, colitis and colon cancer.

The study is the first to investigate the response of gut microbiome - the term for the population of microbes in the intestine - during military training.

It looked at a group of 73 Norwegian Army soldiers taking part in a military-style cross country skiing training programme.

The group skied 31 miles (51 km) while carrying 99-pound (45 kg) packs, across four days. Before and after the training
exercise, researchers collected blood and stool samples from the soldiers.

It was found that the microbiome and metabolites - the substance formed in or necessary for metabolism - in the soldiers' blood and stool altered 'significantly' by the end of the aggressive training period.

Furthermore, sucralose excretion in their urine samples rose considerably, indicating an increase in intestinal permeability (IP).

Scientists know that healthy intestines have a semi-permeable barrier, which acts as a defense to keep bacteria and other harmful substances out, while allowing healthy nutrients into the bloodstream.