The Science behind “Cells at Work!!” Episode 8: “Cancer Cell II (Part II)”

In this episode, toxic gases from harmful bacteria in the colon allow Cancer Cell to grow stronger. However, as the Lactic Acid Bacteria arrive in the colon to eliminate the harmful bacteria, the toxic gases disappear, causing Cancer Cell to become weaker. At the same time, Memory T Cell performs his ultimate technique, T Cell Perforin Cannon Punch, to fire a beam that damages Cancer Cell. The beam also wipes away the label on Cancer Cell’s shirt, prompting Regulatory T Cell to recognise him as an enemy and turn against him. Without the protection of Regulatory T Cell, Neutrophil, who breaks out of his pod, easily kills Cancer Cell, ending the threat.

To learn more about Memory T Cell’s ultimate technique, see this blog post from season 1 of the anime where I explain what cancer is and how T and NK cells can kill cancer cells. I also explained in the last blog post how the immune system can be suppressed to promote the growth and metastasis of cancer. In this blog post, I will talk about colorectal cancer which is where the last two episodes of season 2 takes place. I will explain how common colorectal cancer is, how it develops and how it is treated. I will then talk about the role of the gut microbiota and the various metabolites in increasing or decreasing the risk of colorectal cancer.

How common is colorectal cancer? 

Colorectal or bowel cancer is cancer that grows in any part of the colon, including the rectum, the last section of the colon before the anus. Colorectal cancer is a common cancer globally that causes a lot of deaths. It is estimated that globally in 2020, colorectal cancer was the third most commonly diagnosed cancer, accounting for 10.0% of all cancer diagnoses (1.9 million new cases), and the second leading cancer-related cause of death, accounting for 9.4% of all cancer deaths (935,000 deaths). Colorectal cancer occurs most often in developed countries in Europe, Australia/New Zealand and North America, but the number of new cases and deaths of colorectal cancer is projected to increase in the future, particularly in emerging countries such as Brazil and China. 

There are some intrinsic risk factors that inherently increase the risk of people developing colorectal cancer. These include those with a family history of colorectal cancer (several close relatives having colorectal cancer), hereditary conditions such as familial adenomatous polyposis (FAP) or a past history of chronic ulcerative colitis or Crohn’s disease. The adoption of a sedentary lifestyle has also produced a range of modifiable risk factors that can increase the risk of colorectal cancer. These include consumption of a high fat, high sugar diet, particularly on red and processed meats, excessive alcohol consumption, no or little physical activity, overweight and obesity and smoking. The risk of developing or dying from colorectal cancer can be reduced by modifying one’s lifestyle. For instance, exercise and physical activity and a high fibre diet have been shown to reduce the risk of developing or dying from colorectal cancer. 

How does colorectal cancer develop?

Colorectal cancer develops over 10-40 years as a series of mutations, DNA damage and chromosomal instability (rearranging or merging sections of different chromosomes). These genetic events can lead to some intestinal epithelial cells to proliferate uncontrollably. Colorectal cancer initially starts as polyps, small bumps on the inner layer of the colon produced by rapidly proliferating cells. Most polyps are benign or not cancerous. However, as cells in the polyp accumulate more mutations and as the polyp is constantly exposed to physical trauma and hypoxia, the polyp becomes chronically inflamed due to the accumulation of white blood cells. Inflammation, combined with uncontrolled proliferation of cancer cells, transforms the polyp into a tumour mass that can grow into the colon lumen and through the layers of the colon. If the tumour mass is not removed, some cancer cells may break off from the tumour mass and metastasise to nearby lymph nodes or distant organs via the lymphatic vessels or the bloodstream. 

Different stages of colorectal cancer describe the progression of the cancer. The stage that the colorectal cancer has reached is dependent on:

1. The extent in which the tumour penetrates through the layers of the colonic wall; 
2. Whether cancer cells have migrated to nearby lymph nodes; and
3. Whether cancer cells have established metastases in distant organs. 

The stages of colorectal cancer, as defined by the AJCC (American Joint Committee on Cancer), are as follows:

1. Stage 0: the tumour mass is restricted to the mucosa, the innermost layer of the colon.
2. Stage 1: the tumour mass penetrates through the submucosa and muscularis propria (muscle layer), the middle layers of the colon.
3. Stage 2: the tumour mass penetrates through all layers of the colon, including the serosa which is the outermost layer of the colon. Cancer cells from the tumour mass may also invade the visceral peritoneum, a membrane that wraps around organs in the abdominal cavity, to spread to other organs. 
4. Stage 3: cancer cells from colorectal cancer can be found in nearby lymph nodes. The number of lymph nodes involved can influence prognosis, with an increased number associated with reduced survival rates of colorectal cancer.
5. Stage 4: colorectal cancer undergoes metastasis, where cancer cells from the tumour mass spread through the lymphatic vessels or bloodstream to distant organs. There, they will establish and grow new tumour masses, mostly in the liver and the lung. 

Symptoms of colorectal cancer include: 

• Bleeding from the anus;
• Abdominal pain;
• Changes in bowel patterns, resulting in diarrhoea or constipation;
• Weight loss; and
• Anaemia, a reduced number of red blood cells in the blood. 

How is colorectal cancer screened and treated? 

If detected early, colorectal cancer is highly treatable. Screening programs allow colorectal cancer to be detected early while the person is asymptomatic. Most screening programs use either the faecal occult blood test (FOBT) or faecal immunochemical test (FIT), both of which involve the person taking samples of the stool at home and sending them to a testing centre. In these testing centres, stool samples are screened for invisible traces of blood, detected by a chemical reaction for FOBT or antibodies for FIT. If traces of blood are found in the stool (detected by a colour reaction for FOBT or double lines for FIT), then a colonoscopy is commonly performed to confirm the presence of colorectal cancer. This involves using a colonoscope to view the entire colon and take biopsies, samples of an abnormal-looking bowel, to check for cancer cells. Alternatively, the abdominal cavity can be imaged or scanned with an x-ray or computed tomography to examine for the presence of tumour masses in the colon. 

If cancer cells or tumour masses are detected in the colon, the most common way to treat, and possibly cure, colorectal cancer is surgery. This involves making a keyhole or an opening in the abdominal cavity to remove the tumour mass in the colon and surrounding lymph nodes. Surgery is commonly accompanied by chemotherapy, using drugs to kill cancer cells, and/or radiotherapy, using x-rays to kill cancer cells. Either or both can be given before surgery to reduce the size of the tumour that needs to be removed (neoadjuvant treatment) or after surgery to eliminate any remaining cancer cells that could cause relapse or spread to other organs (adjuvant treatment).

What is the role of the microbiota in colorectal cancer?

In the episode, the harmful bacteria had an influence on Cancer Cell’s strength. When they were present, Cancer Cell was strong and was able to proliferate rapidly. However, when the harmful bacteria were defeated by Lactic Acid Bacteria, Cancer Cell became weaker, allowing him to be defeated by Neutrophil. The gut microbiota has a huge influence on a person’s risk to colorectal cancer. In fact, dysbiosis, where there are more harmful bacteria and less beneficial bacteria, can contribute to the development of colorectal cancer. Some harmful bacteria in the gut microbiota have not only been shown to be more prevalent in colorectal cancer patients, but their contribution to colorectal cancer has also been well-studied. For example: 

• Fusobacterium nucleatum attracts white blood cells to the tumour, enhancing inflammation to accelerate the development of colorectal cancer. The bacterium also secretes a virulence factor called FadA. FadA binds to and cleaves E-cadherin, a tumour suppressor protein, stimulating uncontrolled cell proliferation. As E-cadherin is also important for joining cells, cleaving E-cadherin also degrades the gut epithelium barrier as the intestinal epithelial cells separate. This increases the permeability of the gut epithelium to allow more bacteria to enter the body and alter immune activity. 
• Enterotoxigenic Bacteroidetes fragilits (ETBF) releases fragilysin, a toxin that binds to and cleaves E-cadherin. This leads to uncontrolled cell proliferation and increased permeability of the gut epithelium, both of which contribute to colorectal cancer development. Fragilysin also boosts NF-κB signalling inside intestinal epithelial cells, damaging DNA and increasing pro-inflammatory cytokine secretion. 
• Escherichia coli can release various toxins such as cytolethal distending toxin and colibactin to damage DNA, contributing to colorectal cancer. 
• Enterococcus faecalis produces superoxide anions, reactive oxygen species that can stimulate macrophages in the gut epithelium to produce chromosomal-breaking factors. These factors, when released, can contribute to chromosomal instability and DNA damage in intestinal epithelial cells, transforming them into cancer cells.
• Streptococcus gallolyticus is notable because it is prevalent in not only the colon but also the bloodstream in colorectal patients. This bacterium possesses a number of features that enable it to colonise and grow around colonic tumours. The bacterium also produces COX-2 to enhance inflammation, contributing to colorectal cancer. 

In short, harmful bacteria in the colon can contribute to the development of colorectal cancer by damaging DNA, stimulating uncontrolled cell proliferation and/or activating inflammation.

What are the roles of metabolites and probiotics in colorectal cancer?

The gut microbiota can process food in the colon to produce metabolites. These metabolites can increase or decrease the risk of colorectal cancer which in turn mediate the effects of different diets. 

Consuming a diet that is high in red meat and saturated fats can increase the risk of colorectal cancer by producing metabolites that promote carcinogenesis and inflammation, represented by the toxic gases in the episode. A diet high in red meat produces excessive amounts of amino acids which are degraded to toxic nitrogen and sulfur metabolites. One of these nitrogen metabolites is ammonia which, in high concentrations, is toxic to cells and promotes inflammation and epithelial cell proliferation. Bacteria in the gut microbiota can also convert nitrogen and sulfur metabolites from amino acids to N-nitrosamines which are potent carcinogens and to various phenolic compounds, indoles and p-cresol which have been shown to increase the permeability of the intestinal epithelium. 

High saturated fat intake leads to increased production of bile acids cholic and chenodeoxycholic acid in the liver. In turn, these bile acids are converted to lithocholic and deoxycholic acid by gut bacteria in the small and large intestines. Lithocholic and deoxycholic acids can promote inflammation by acting on intestinal epithelial cells to activate NF-κB and stimulate production of reactive oxygen and nitrogen species. Both of these events damage DNA, contributing to the development of colorectal cancer.

There are also various nutrients and metabolites that can reduce the risk of colorectal cancer. Consumption of a high fibre diet (> 50g/day) is associated with a reduced risk to colorectal cancer. As explained in a previous blog post, fibre is fermented by gut bacteria in the colon to short-chain fatty acids (SCFAs) such as butyrate, propionate and acetate. SCFAs play an important role in reducing the risk of colorectal cancer. SCFAs have an anti-inflammatory effect on white blood cells to limit inflammation, boosting the activities of regulatory T cells and IL-10 to suppress immune responses. They also prevent uncontrolled proliferation of intestinal epithelial cells. Butyrate acts as the preferred energy source for colonocytes, ensuring that they stay alive and can function normally. In contrast, acetate and propionate are absorbed into the body to control metabolism, including suppressing cholesterol production and weight gain which can increase the risk of colorectal cancer. 

Phytochemicals are micronutrients found in fruits, vegetables, grains and high-fibre foods that have antioxidant and anticancer effects. For example, polyphenols, found in grapes, tea, coffee and cocoa, can prevent cancer. They have anti-inflammatory, anti-proliferative and anti-cancerous effects in the colon by inhibiting inflammation and stimulating the production of enzymes that degrade toxins in the colon. Resveratrol in red wine and non-alcoholic red wine can also promote the growth of healthy bacteria such as Prevotella and Bifidobacterium which are shown to reduce the risk of colorectal cancer. 

Lastly, probiotics such as Lactobacillus (which are represented in the anime) and Bifidobacterium may act to supplement treatments against colorectal cancer. The administration of probiotics in rats and humans has been shown to reduce the risk of developing colorectal cancer by inducing cancerous cells to die, inhibiting secretion of pro-inflammatory cytokines such as IL-2 and IFN-γ to limit inflammation, increasing the amount of tight junction proteins to strengthen the intestinal epithelial barrier and enriching the diversity of the microbiota to limit the growth of harmful bacteria. Probiotics may also reduce the severity of side effects such as diarrhoea and abdominal pain associated with cancer treatments such as radiotherapy and chemotherapy.

Conclusion

Colorectal cancer is a common and, if not detected and treated early, deadly disease. Colorectal cancer develops over a number of years, where intestinal epithelial cells accumulate mutations, DNA damage and chromosomal instability to become cancer cells. These cancer cells can establish tumour masses that grow over all layers of the colon and may metastasise to nearby lymph nodes and distant organs. As the anime episode shows, the composition of the gut microbiota can influence the risk of colorectal cancer. While there are some harmful bacteria that can contribute to the development of colorectal cancer, there are also some beneficial bacteria that can prevent or reduce the risk of colorectal cancer. Diet and probiotics, when combined with conventional cancer treatments such as surgery, chemotherapy and radiotherapy, may supplement efforts to eliminate colorectal cancer, prolong life and enhance quality of life among colorectal cancer patients. 

That is it for “The Science behind Cells at Work!!” series. I hope that you enjoyed the series and learnt something fantastic about the human body. I hope to see you again in a future blog post!