Previously described in ancient Egypt before being named after a crab or crayfish (Greek: καρκίνος) by Hippocrates, cancer is a term which is familiar to everyone as a major disease in humans.
Although people may be aware of the risks that cancer may impose on human health, what do we actually mean when we refer to cancer, and how does this condition affect the human body?
What is cancer?
To begin with, cancer is a collection of related diseases and can be described as the uncontrollable growth of cells in a specific region of our body.
What are the main variants of cancer?
The different types of cancer can be categorised based on the types of cells that they arise from. To keep things simple, there are seven main categories in which cancers can be categorised.
The first category is carcinoma, which arises from epithelial cells (i.e. cells lining the internal and external surfaces of our body) and is one of the most prevalent types of cancer. To go into a little more detail, carcinomas that are formed from different types of epithelial cells are given unique names - for example, cancer that emerges from fluid- or mucus-producing epithelial cells (a.k.a. glandular/secretory cells) are classified as adenocarcinoma.
Moving on, the second main type of cancer is sarcoma, which can arise from our bones (e.g. osteosarcoma) or other soft tissues (e.g. Kaposi sarcoma) such as muscles, fat, or blood vessels.
Besides that, another category of cancer is leukemia, which emerges from the blood-forming tissue of the bone marrow. Interestingly, this category of cancer does not generate tumours. Instead, they cause the crowding of abnormal white blood cells in our bone marrow and blood, thereby disrupting the normal blood circulation by obstructing normal blood cells from doing their job.
Meanwhile, we have lymphoma as the fourth type of cancer. This type of cancer arises from white blood cells that are involved in fighting off diseases - lymphocytes (i.e. T and B cells). There are two main types of lymphoma, namely Hodgkin lymphoma and Non-Hodgkin lymphoma - both of which causes an abnormal accumulation of lymphocytes within the patient’s lymph vessels and lymph nodes in addition to other organs.
Next on the list is multiple myeloma, which arises from another variant of immune cell known as plasma cells (which are derived from B cells). In particular, myeloma involves the accumulation of plasma cells in the bone marrow, which thereby contributes to the development of tumours within the bones across our body.
Moreover, the sixth type of cancer is melanoma. It arises from melanocytes (i.e. cells responsible for the pigmentation of our skin). The majority of melanoma cases originate from the skin, but other pigmented tissues like our eyes may also serve as a starting point.
Finally, the last category of cancer would be the brain and spinal cord tumours. This type of cancer involves the development of tumours within our central nervous system, and the subcategories of this form of cancer are named after the regions and the cell types they have emerged from.
Malignant vs. benign
Besides categorising cancer into the various classes that were mentioned above, cancer can also be separated into either malignant and benign.
Benign tumours are made of cells that closely resemble and share similar functions as normal cells. They are usually not life-threatening unless they cause any disruptions to the normal functioning of our organs (e.g. they could trigger the excessive production of hormones).
In contrast, malignant tumours are composed of cells that are dividing and differentiating very quickly. The key distinguishing feature of malignant tumours is their ability to perform metastasis (unlike benign tumours that couldn’t). This is a process whereby malignant tumour cells exit their main site of growth and spread to different areas in the body (known as secondary sites).
The hallmarks of cancer
Scientists have been conducting extensive research over the years to determine the factors contributing to cancer development. Or more specifically, they wanted to identify the specific physiological alterations a cell undergoes that results in the development of malignancy. Fast forward to today, they eventually manage to come up with six hallmarks of cancer as an explanation (check out Figure 1).
The six hallmarks of cancer
The first hallmark refers to the cancer cell’s ability to maintain chronic proliferative signaling. Cancer cells achieved this by deregulating growth-promoting signals so that they would be able to gain full control of their own fate. Next, the second hallmark refers to the evasion of growth suppressors so that the cancer cells are able to continue proliferating without any restrictions. Given that the first two hallmarks are arguably the same thing as they both lead to a state of chronic proliferation, it is important to note that some researchers do group them together so they are presented as one hallmark.
Moving on, the third cancer hallmark is the evasion of programmed cell death (a.k.a. apoptosis) by cancer cells. Cancerous cells can avoid apoptosis by upregulating the production of specific anti-apoptotic proteins (i.e. proteins that inhibit apoptosis) or by downregulating pro-apoptotic proteins (i.e. proteins that promote apoptosis). What’s more, even if cancer cells do get apoptotic, the necrotic tissue (i.e. dead or devitalized tissue) left can also contribute to the development of cancer due to its ability to attract immune components that can further promote tumour development.
Meanwhile, the fourth hallmark is replicative immortality, which refers to the ability of cancer cells to overcome the processes of senescence (the cell losing its ability to proliferate and grow despite remaining alive) and crisis (the cell dies) by maintaining telomeric DNA at specific lengths. However, it is important to note that recent revisions have categorized the third and the fourth hallmarks together as they both lead to altered stress responses.
Furthermore, the fifth hallmark of cancer is identified as the ability to trigger angiogenesis. Just like normal cells, tumour cells need ample amounts of nutrients and oxygen as well as a metabolic waste removal system in order to survive. The process of angiogenesis, therefore, fulfills all these demands as it induces the formation of vasculatures (a network of blood vessels) to facilitate the delivery of oxygen and nutrients to newly formed tumours. This process involves various growth factors such as vascular endothelial growth factor-A (VEGF-A).
Finally, the sixth hallmark is the activation of invasion and metastasis. This is achieved through the initiation of a developmental regulatory programme called the epithelial-mesenchymal transition (EMT). In essence, the programme allows cancer cells to disseminate, invade other tissues as well as escape apoptosis - all of which are accomplished with the help of various transcription factors (called Snail, Slug, Twist, and Zeb1/2), proteins that activate or switch off certain genes. As a result, metastasis can take place.
Emerging hallmarks
Even with these six hallmarks, researchers have also identified two emerging hallmarks. In essence, they are called “emerging” hallmarks because they have not been completely validated and generalised by researchers yet (or at least at the point of writing).
The first one is the cancer cell’s ability to reprogramme/modify cellular energy metabolism so that it is optimised for neoplastic proliferation. Meanwhile, the second emerging hallmark is the ability of cancer cells to evade our immune system (and thereby destruction).
Additionally, it was also argued that the common characteristics of these two additional hallmarks are the presence of genome instability (which contributes to an increased likelihood of mutations amongst cancer cells) and tumour-promoting inflammation that is initiated by the immune system.
Figure 1: Present and emerging hallmarks of cancer. The original six hallmarks of cancer are shown on the left. As the research progressed, several researchers have proposed two additional hallmarks of cancer, which are shown on the right. This figure was adapted from Weinberg et al. (2011).
How does cancer arise?
Although cancer development may be considered by many to be a one-step process, that is actually incorrect.
In fact, cancer development consists of multiple processes that mainly involve genetic changes (i.e. mutations). These mutations can occur either in the germ cells - called germline mutations (we inherit them from our parents) or in different tissues throughout a person’s lifetime – called somatic mutations. In somatic mutations, the mutations occur mainly in proto-oncogenes - they are genes associated with the regulation of cell division. Hence, a mutation in them would result in uncontrollable cell division, leading to tumour formation.
In addition, compounds and substances that we can come in contact with in our everyday lives can also induce cancer development. Such substances can be tobacco smoke or even direct sunlight (ultraviolet light) - all these compounds have been found to have tumour promotion effects mainly by inducing mutations.
On top of these, viruses have also been found to cause cancer in humans. In particular, studies have demonstrated that the human papillomavirus (HPV), Epstein-Barr virus (EBV), as well as hepatitis B and C viruses (HBV, HCV), are involved in cancer development through infections.
To shift gears slightly, here’s a mini fun fact. Did you know - the Nobel Prize of Physiology or Medicine 2020 was awarded to Harvey J. Alter, Michael Houghton, and Charles M. Rice? They are the scientists that discovered the hepatitis C virus!
Why are cancer cells so resistant in the human body?
Apart from the present and emerging hallmarks that contribute to cancer development, another very important process has been observed to occur in tumour environments. This process is called immunoediting (check out Figure 2).
To elaborate, immunoediting is a process by which cancer cells acquire new mutations so that they can avoid being recognised by the cells of our immune system. This eventually makes them more resistant to destruction.
There are three phases in this process, namely the elimination phase, the equilibrium phase, and the escape phase.
The elimination phase, as its name suggests, refers to the state in which the immune system has recognised and targeted the cancerous cells, resulting in their destruction.
The problem is that the immune system may not completely eliminate the cancer cell population. This thereby gives some tumour cells the opportunity to mutate and to continue dividing and developing.
To combat this, the immune system suppresses the newly mutated cancer cells from proliferating any further by applying external pressure - for instance, the production of toxic compounds such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). This phase is called the equilibrium phase of immunoediting and is defined as the constant effort of the immune system to contain tumour growth.
Nevertheless, new (and even more resistant) cancer cells may still arise through the acquisition of new mutations. These mutations thus help them to avoid the recognition and the suppression by our immune system. With that in mind, the last phase is labelled as the escape phase, which describes the stage in which cancer cells have successfully avoided the immune system’s oppression entirely.
Figure 2: The phases of immunoediting. In the elimination phase, the tumour cells arise whilst the cells of the immune system begin their destruction plan via antigen recognition. In the equilibrium phase, the immune system does its best to contain the cancerous cells, but if the containment is unsuccessful, newly mutated tumour cells may arise. Finally, in the escape phase, these mutated tumour cells, which have now completely escaped recognition by the immune system, can divide and contribute to the development of cancer.
Why should you care?
Now that we understand what cancer is and how it functions in the human body, it is crucial to look at this disease from a broader context. In humans, cancer has a very high prevalence. As a matter of fact, more than 18.1 million cases and 9.5 million cancer-related deaths were recorded in 2019 alone!
As we mentioned previously, there are many factors that contribute to cancer progression, with one of them being the environment. Therefore, raising public awareness of protecting oneself from constant exposure to carcinogenic (cancer-inducing) compounds is vital.
What’s more, it is crucial to understand that the current treatments against certain types of cancer - including surgeries, chemotherapies, and radiotherapies - may not always work out the way we would have wanted them to.
Therefore, a sound understanding of cancer biology as well as how our immune system combats it would be crucial in order for us to design novel and creative approaches to halt or delay cancer development.
Author
Filippos Maniatis
BSc Biological Sciences, Imperial College London
MSc Bioscience Entrepreneurship, UCL
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