Cancer Cells

Globally, cancer is the second leading cause of deaths, with every 1 in 6 deaths being linked to the disease. As of 2018, 9.6 million people have lost their lives to cancer. So, how is cancer such a deadly disease? What makes a cancer cell so dangerous?

The term ‘cancer’ is a generic term used to categorize a group of diseases that are characterised by the uncontrolled division of abnormal cells in the body, otherwise known as cancerous or metastatic cells. Cancer can also be referred to as a neoplasm, which is defined as a new and abnormal growth of tissue in some part of the body, or a tumour, which is a swelling without inflammation in a part of the body that can be caused by an abnormal growth of tissue. Tumours can be benign, where the abnormal cell growth is limited to a certain area or malignant, where abnormal growths are capable of spreading to other parts of the body and forming secondary tumours. This occurs when parts of the primary malignant tumour break off and travel through the bloodstream to other parts of the body.

Essentially, a benign tumour is non-invasive and non-cancerous while a malignant tumour is invasive and cancerous.

Risk factors

Cancer is a genetic disease caused by an accumulation of detrimental variation in the genome over a lifetime. Some major risk factors that could increase the likelihood of an individual developing cancer are:

• Tobacco use

• Alcohol consumption

• Physical inactivity

• An unhealthy diet rich in sugar and fat

• Obesity

• Exposure to excessive amounts of ionising and/or UV radiation.

Types of cancer

There are four main types of cancer, which are classified according to the tissue in which they originate.

• Sarcomas - cancers which arise from the connective tissue found in bones, tendons, cartilage, muscle and fat

• Leukemias - cancers of the blood which originate in the bone marrow.

• Lymphomas - cancers of the lymphatic system.

• Carcinomas - cancers which arise in the epithelial tissue found in the internal or external lining of the body.

The different types of cancers are more broadly referred to by the region of the body where the primary tumour forms, eg. breast cancer, lung cancer, liver cancer etc.

Cancer prognosis

There are many different factors which influence the prognosis of cancer in each patient. These factors include:

• The type of cancer

• The location of the cancer

• The stage of the cancer

• The patient’s age and general health condition at the beginning of therapy

• The response of the cancer to treatment

Hallmarks of cancer cells

The hallmarks of cancer cells are characteristics of cancer cells which render them ‘fit’ to survive, reproduce rapidly, and compete with normal cells in the body. There are ten main cellular hallmarks of cancer cells. These are:

1. Replicative immortality

2. Genome instability

3. Evasion of growth suppressor signals

4. Resistance to cell death

5. Sustained proliferation

6. Altered metabolism

7. Avoiding immune destruction

8. Tumour-promoting inflammation

9. Induction of angiogenesis

10. Activation of invasion and metastasis.

Hallmark no. 1 - replicative immortality

Replicative immortality means that a cancer cell is able to divide and reproduce unlimitedly by the process of mitosis. Normal cells have a finite ability to undergo mitosis due to something called the end replication problem. The end replication problem is due to the fact that the ends of linear DNA cannot be copied fully, resulting in the ends of chromosomes (telomeres) shortening after each division. Eventually the telomeres will be too short for the cell to undergo mitosis. When this point is reached, the cell is said to have reached Hayflick’s limit. Cancer cells are able to greatly exceed Hayflick’s limit and continue to undergo mitosis. This is due to their ability to elongate their telomeres using an enzyme called telomerase. The replicative immortality of cancer cells is crucial for their survival and reproduction, as it allows them to continuously proliferate and pass on mutated genes to daughter cells.

Hallmark no. 2 - genomic instability

Genomic ability refers to the increased tendency for genome alteration during cell division in a cancer cell. If a mutation is detected in a normal cell undergoing DNA synthesis, the cell cycle will arrest and the mutation will be repaired before re-entering the cell cycle. This is done by genes named tumour suppressor genes. Cancer cells have abnormal amounts of chromosomes per cell and can bear mutations in their DNA with the ability to still undergo mitosis. This is because tumour suppressor genes are commonly mutated or lost in cancer cells. Additionally, genes called oncogenes are often overexpressed in cancer cells, causing them to proliferate uncontrollably. Genomic instability allows for cancer cells to undergo unhindered replication despite their genetic mutations and spread to other parts of the body.

Hallmark no. 3 - evasion of growth suppressor signals

The evasion of growth suppressor signals allows cancer cells to undergo uncontrolled division. In normal cells, mitosis is tightly controlled due to pro-proliferation and anti-proliferation signals coordinating cell activities at the cell cycle level.However, cancer cells can circumvent normal growth suppressor cells in the G1 stage checkpoint of the cell cycle, in order to continue proliferating. They are able to do so due to hallmark no. 2 - genomic instability.

Hallmark no. 4 - resistance to cell death

Resistance to cell death means that cancer cells are less likely to undergo the process of apoptosis (cell death) in comparison to normal cells. Normal cells can initiate apoptosis in response to abundant DNA damage and other cellular stresses. Cancer cells are less sensitive to abundant DNA damage, growth factor deprivation, cancer treatments, and similar stresses. Cancer cells are also able to increase the regulation of pro-survival proteins. These are the main reasons why cancer cells tend to avoid apoptosis. The resistance to cell death in cancer cells allows them to survive in the body and reproduce further, eventually resulting in the growth of a tumour.

Hallmark no. 5 - sustained proliferation

Sustained proliferation refers to a cancer cell’s ability to divide and reproduce to a greater extent in comparison to normal cells, where growth factor signalling is tightly controlled. Cancer cells can stimulate normal cells in the tumour microenvironment (the environment surrounding the tumour) to provide growth factors, allowing them to sustain proliferation. This enables cancer cells to reproduce in the body, leading to increased chances of survival.

Hallmark no. 6 - altered metabolism

Altered metabolism is important when it comes to supporting sustained proliferation. For cancer cells to sustain uncontrolled cell proliferation, the cells must adjust their energy production accordingly to obtain additional sources of nutrients and energy in comparison to normal cells. They can do this by finding and using alternate energy sources and alternative metabolic pathways. Normal cells typically break down glucose into pyruvate by the process of glycolysis. Pyruvate produces adenosine triphosphate (ATP) for the cell and therefore a source of energy. Cancer cells can convert glucose to lactate irrespective of oxygen. This allows cancer cells to divert metabolites for essential processes such as mitosis, which is crucial for the reproduction and survival of cancer cells in the body.

Hallmark no. 7 - avoidance of immune destruction

Avoidance of immune destruction means that cancer cells have adopted mechanisms to prevent being detected by the immune system and prevent themselves from being destroyed. The immune system surveils the human body to destroy any foreign cell types, including tumour cells. Cancer cells protect themselves by inhibiting certain immune cell types, such as T-lymphocytes. This is done by up-regulating a protein called programmed death-ligand 1 (PDL1) which plays a major role in suppressing the immune system during pregnancy, autoimmune diseases, hepatitis and other disease states. By up-regulating this protein, cancer cells are able to suppress immune response and avoid immune destruction, allowing them to survive in the body.

Hallmark no. 8 - tumour promoting inflammation

Tumour promoting inflammation means that cancer cells utilise the inflammatory mechanisms of the immune system to support their own growth within the body. The tumour microenvironment is often infiltrated by cells from the immune system that enable tumours to mimic inflammatory conditions seen in normal tissues. Immune cells provide the tumour cells with essential factors that allow them to survive, move, proliferate and invade tissues in the body.

Hallmark no. 9 - induction of angiogenesis

Angiogenesis refers to the formation of blood vessels within the body. Hence, the induction of angiogenesis means that cancer cells have mechanisms to form new blood vessels from pre-existing blood vessels in order to obtain the nutrients needed by the tumour to grow to a significant size. Tumour cells are geographically further away from the blood vessels than normal cells as they have a faster growth rate. As a result, tumour cells outgrow their source of nutrients such as oxygen and glucose. Thus, new blood vessels need to be made by angiogenesis in order to reach the tumour cells. These newly formed tumour blood vessels tend to be leaky, thereby providing a way for tumour cells to enter the bloodstream and lymphatic vessels. Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) become activated in tumour cells. Immune infiltrating cells such as macrophages can also secrete VEGF to induce angiogenesis. Both of these features assist the process of angiogenesis in cancer cells, enabling the cancer cell to survive and compete with other cells in the body.

Hallmark no. 10 - activation and invasion of metastasis

The final hallmark of cancer cells is the activation of invasion and metastasis. The first nine hallmarks equip cancer cells with the necessary materials and mechanisms required to spread to multiple parts of the body and form secondary tumours by metastasis. There are four key steps of the metastatic process:

1. Invasion - tumour cells break through the extracellular matrix and migrate outwardly, away from their natural location, enabling them to move towards blood vessels.

2. Intravasation - tumour cells enter the blood, either actively by pushing their way through endothelial cells, or passively, by tumour cells being shed from a tumour and entering presumably leaky blood vessels.

3. Survival during systemic circulation - tumour cells circulating through the bloodstream must work to avoid various sources of cell death.

4. Extravasation - tumour cells begin growing in the secondary site into metastatic tumours. These cells may not begin to divide immediately when they reach their destination, but may become dormant and grow into a tumour later.

Cancer cell hallmarks in research

Why are each of these hallmarks important in cancer research? Studying these hallmarks allows for treatments to be devised to target these hallmarks and prevent cancer cells from surviving in the body. For example, scientists have been able to exploit hallmark number nine

(induction of angiogenesis) to develop drugs called angiogenesis inhibitors. These drugs block the formation of new blood vessels in cancer cells, aiming to slow the growth of tumours by starving them of the nutrients they require to grow. Other examples of such drugs include antimetabolites used in chemotherapy, which exploit hallmark number six (altered metabolism) in order to inhibit certain metabolic pathways in cancer cells, and mitotic inhibitors, which exploit hallmarks number one (replicative immortality) and three (evasion of growth suppressor signals). While there is no cure for cancer yet, research into cancer cell hallmarks has provided a clear direction for scientists to move in to find an effective treatment option.

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