Over one and a half episodes, Neutrophil, Killer T Cell and NK Cell battle against Cancer Cell. It all starts when, after killing a cancer cell, they are escorted by a normal cell to an abandoned building. Neutrophil and Killer T Cell explore the building, where they find cancer cells endlessly proliferating, not following the normal proliferation program. Meanwhile, NK Cell takes the normal cell aside where she reveals that he is really Cancer Cell. The white blood cells are bombarded by cancer cells and are beaten up by Cancer Cell as the building collapses. They are saved; however, by immune cells brought together by Red Blood Cell to kill the cancer cells, ending the threat.

What is cancer and how does the immune system prevent cancers from growing and spreading? Find out as we delve deeper into the topic of cancer.

Cancer: what is it and how does it arise?

Schematic	Microscopic	Anime

Cancer arises from normal cells that have transformed into cancer cells. These cancer cells grow and divide uncontrollably, overcoming the normal limits of cell growth and division to establish a tumour in an organ. Some cancer cells may break off from the tumour to spread cancer to distant organs in a process called metastasis.

Normal cells transform into cancer cells by accumulating multiple mutations over a period of time. These mutations are encapsulated in Hanahan and Weinberg’s Hallmarks of Cancer. There are seven hallmarks that are associated with the development of cancer (note that the sixth hallmark is split into two to more clearly delineate separate processes):

1. Sustained proliferative signalling: normal cells can only grow and divide if they receive appropriate growth signals from the outside of the cell. Mutations in cancer cells allow them to respond to their own growth signals to grow and divide by themselves without external stimuli.
2. Evading growth suppressors: normal cells stop growing and dividing by responding to anti-growth and anti-proliferation signals. In contrast, cancer cells mutate genes that allow them to become unresponsive to anti-growth and anti-proliferation signals. Combined with their ability to respond to their own growth signals, cancer cells are able to overcome the normal limits of proliferation to continuously grow and divide.
3. Resisting cell death: if there are too many normal cells, cells are directed to die by apoptosis. Mutations in cancer cells make them less responsive to cell death, allowing dividing cancer cells to survive longer.
4. Enabling replicative immortality: even when a cell can continuously divide, the number of times it can do so is limited by the length of telomeres present at the end of chromosomes. As soon as the telomeres are short, cells stop dividing and start dying one-by-one. However, by overexpressing an enzyme called telomerase to maintain telomere length, cancer cells can become immortal, allowing them to divide an unlimited number of times.
5. Inducing angiogenesis: cancer cells require a massive amount of nutrients and oxygen to continuously grow and divide, shown by the huge influx of supplies delivered to the abandoned buildings in the anime. This can be accomplished by releasing factors that promote the growth of new blood vessels. This process, called angiogenesis, allows more nutrients and oxygen to be delivered to the growing tumour.
6. Activating invasion: as the tumour grows, some cancer cells become detached from the tumour and normal tissue. These cells also acquire the ability to release enzymes and proteins that allow them to move through the tightly-packed tissue.
7. Metastasis: cancer cells move towards blood and lymphatic vessels in the local tissue. Once there, they enter blood and lymphatic vessels to spread around the body. Cancer cells are able to establish small colonies in distant organs which eventually become tumours, spreading the cancer elsewhere.

What would a typical cancer patient display?

Depending on where the tumour or cancer is grown, the symptoms of cancer and how people die of cancer can vary. Typical symptoms of cancer include:

1. Weight loss and fatigue: cancer cells consume a lot of the body’s oxygen and nutrients to endlessly grow and divide, diverting them away from normal cells around the body. Cancer cells also release factors that alter the body’s metabolism. This not only leads to weight loss as the body’s energy stores are depleted to grow the cancer but also fatigue as normal cells cannot function properly. Weight loss is particularly prominent in pancreatic, stomach and lung cancers.
2. Pain: this arises from a large tumour pressing on a nearby organ, blood vessel or nerve. While pain can be localised such as back pain in colon and ovarian cancers, pain felt all around the body could be a sign of metastasis to multiple organs.
3. Presence of blood in urine or stools: this is a typical sign in colon, bladder and prostate cancers as urine or stools are passed through a bloody tumour mass.
4. Change in colour, size or shape of wart, mole or freckle: this is a typical sign of melanoma. Cancer cells in the skin become disorganised as they grow and divide, forming a tumour mass on the skin that can be observed.

Most people die of cancer as a result of healthy organs and tissues not being able to function properly. As cancer cells endlessly grow and divide, less of the body’s oxygen and nutrients are consumed by healthy cells which impedes normal function. This can be exacerbated when the body becomes incapable of extracting nutrients or energy from food in gastrointestinal cancers such as stomach, pancreatic and colon cancers. Consequently, healthy organs and tissues cannot function properly, leading to death. Bone cancers arising from a primary or metastatic tumour also increase calcium release from bones into the bloodstream. This causes high blood calcium concentrations which can lead to unconsciousness and death.

Immunosurveillance: the immune response to cancer

Immunosurveillance is the idea that the immune system can recognise and kill cancer cells to prevent tumours from growing and spreading. Both killer T and NK cells recognise mutated or overproduced proteins from cancer cells to kill them. However, they recognise cancer cells in different ways. Killer T cells are activated by using their T cell receptor to recognise an epitope loaded on an MHC class I complex on a cancer cell and receiving costimulatory signals (see episode 3 of the blog series for more details of how this occurs).

In contrast, NK cells are activated in the absence of MHC class I complexes on cancer cells. This is a common strategy that cancer cells use to escape being killed by killer T cells. NK cells have two types of receptors: activating receptors that bind to stress ligands on cancer cells and inhibitory receptors that recognise MHC class I complexes. The NK cell is activated when activating receptors recognise stress ligands on a cancer cell but its inhibitory receptors cannot find MHC class I complexes. Hence, NK cells can be used as a backup to kill cancer cells in case killer T cells cannot recognise them due to the lack of MHC class I complexes. This explains why NK Cell but not Killer T Cell was able to identify a normal cell as Cancer Cell in the anime.

Both killer T and NK cells kill cancer cells in two ways. First, activated killer T and NK cells express a protein called FasL which engages with Fas receptors on cancer cells. Signalling pathways inside the cancer cell are activated which allow the cell to die by apoptosis. Second, both cells release perforin and granzyme upon being activated. Perforin forms pores on the cancer cell which granzyme enters to cleave enzymes inside, allowing the cell to die by apoptosis.

It is worth noting that the immune system will react differently to individual cancer cells. This is best described in the middle of episode 7 where Cancer Cell recounts how, as a child, he survived an immune-mediated extermination of cancer cells. Cancer cells that are highly reactive to immune responses will be eliminated first. However, a small population of cancer cells (like Cancer Cell) are weakly immunogenic, so the immune system will be less likely to detect them. These cancer cells can ‘escape’ the immune response to re-establish a tumour in the same or different organ years later, causing relapse of the cancer.

Did you know? The same principle can be applied to chemotherapy as individual cancer cells also react differently to drugs. Drug treatment can eliminate most cancer cells but it can leave a small population of cancer cells that are resistant to it. These cancer cells can re-establish a tumour years after chemotherapy ceases, causing relapse of cancer.

Is laughter the best medicine for cancer?

Towards the end of episode 7, NK Cell has a laughing fit. After that fit, she feels stronger which allows her to cut down Cancer Cell in one hit. The episode says that NK Cell is powered-up because laughter releases chemicals from the brain which increase NK Cell’s activity. Laughter has been shown to reduce anxiety, depression and stress in breast cancer patients and to humanise relationships between doctors and cancer patients, particularly in coping with bad news. However, can laughter really improve NK cell activity enough to kill cancer cells? Biologically speaking, the answer is yes!

When people laugh, the brain releases a chemical called β-endorphin. β-endorphin acts on a variety of cells and tissues to exert beneficial effects such as pain relief. In the context of NK cells, β-endorphins are able to increase NK cell activity in vitro and in vivo, increasing their capacity to kill cancer cells. This is because β-endorphin increases the protein and mRNA production of perforin and granzyme B which enhance NK cell’s cell-killing function. That effect can actually affect the prognosis of cancer, at least in rats. Implanting β-endorphin-producing neurons onto the brains of rats was associated with reduced incidence, growth and metastasis of cancer due to increased NK cell activity and cytotoxicity. Hence, NK Cell does have a scientific basis behind her laughing fits; she has received β-endorphins to increase her ability to kill Cancer Cell.

However, whether laughter therapy can enhance NK cell activity to alter the prognosis of cancer is unclear. This is because there are very few published studies in the area that conflict with one another. Initial published studies found that men and women who laughed in response to a humour video not only had reduced stress but also had increased NK cell activity. In contrast, a later study found that laughter therapy enhanced the quality of life and resilience of breast cancer survivors but did not alter NK cell activity. It should be noted that, in these studies, people had varying responses to the humour stimulus. People that did not laugh at the humour stimulus had reduced NK cell activity while those that did laugh only showed minimal increases. In addition, no recent human studies from 2010 onwards have further investigated the effect of laughter on NK cell activity and the prognosis of cancer. Hence, further studies are required to look at the effects of laughter on NK cell activity and whether they exert significant, long-lasting effects on the prognosis of cancer in humans.

Conclusion: an argument against Cancer Cell’s monologue

In the middle of episode 7, Cancer Cell says some things while beating up the white blood cells. To summarise his monologue, he proclaims that he wants to live just like any other cell and questions why he has to die as a defective cell. Although his monologue asks for sympathy from the viewers, in this conclusion I offer a counter-argument as to why Cancer Cell had to die in the hands of the immune system.

Cancer endangers the lives of not only normal cells but also cancer cells which have received numerous mutations to endlessly grow, divide and spread. This is driven by consuming massive amounts of nutrients and oxygen. Consequently, other cells do not receive enough nutrients and oxygen to function properly which leads to reduced organ function, morbidity and death of the cancer patient. As soon as the cancer patient dies, the cancer cell stops receiving nutrients and oxygen to keep growing and dividing. Unlike pathogens such as bacteria and viruses that can withstand the harsh conditions of the external environment, cancer cells cannot survive outside the human body and cannot spread to other humans. Hence, both normal and cancer cells lose if cancer cells grow and divide unhindered.

The immune system functions to identify and eliminate cancer cells before they form prominent tumours or metastases. Hence, a working immune system can prevent the development of cancer in healthy people, allowing nutrients and oxygen to be equally shared to normal cells to maintain the normal functioning of the human body.

Next time, we will focus on blood circulation and look at how blood delivers oxygen and nutrients to cells and disposes wastes. See you then!