The Development of Cancer - From A Faulty Gene to One Too Many Cigarettes

Oncology is an area of medicine that is continually growing and progressing, due to the complexities of the disease itself. The causes of cancer can be attributed to both genetic and external influences. Given that some risk factors of cancer are preventable, it is possible to limit the rampancy of the illness with the correct oncology education.  Therefore, education on heavily prevalent diseases, such as cancer, is vital to attaining SDG 3: Good Health and Well-being.

Cancer is essentially the result of the uncontrollable proliferation of cells. This leads to the formation of malignant tumours - cancer. Being among the leading causes of death worldwide, oncology can easily be considered one of the most crucial areas of medicine. In 2018 alone, there were 18.1 million new cases and 9.5 million cancer-related deaths worldwide, and the number of new cancer cases per year is expected to rise to 29.5 million by 2040 [1]. These large and ceaseless numbers simply serve as an indicator of how easy it is for something to go wrong within your body for cancer to develop.

The most important factor in cancer development would inarguably be gene mutations. However, it is first necessary to grasp the significance of the structure of DNA in genes before delving into how mutations arise. The DNA molecule forms a double helix structure and is composed of nucleotides. Nucleotides are units consisting of a sugar group, phosphate group, and a nitrogenous base. There are four nitrogenous bases: adenine (A), thymine (T), cytosine (C), guanine (G). These four bases are strung together in a specific way - a genetic code - which allows the ribosome to carry out protein synthesis. A single amino acid is coded for by three nucleotides in a row that form a triplet [2].

Gene mutations are changes in the arrangements of bases in the DNA of a gene and can severely affect the functionality of the impacted cell. It may change the protein that is made so that it does not serve its intended purpose as well, or at all, or it may simply inhibit the protein from being made in the first place. The development of cancer cells is heavily due to these mutations which could potentially affect genes that control cell growth and division. For example, two groups of proteins - cyclins and cyclin-dependent kinases (CDKs) - are in charge of the positive regulation of the cell cycle, and so hence a gene mutation may affect the functionality of these [3] There is a wide range of types of mutations, such as insertions, deletions, and point mutations. Insertions and deletions refer to when a base is incorrectly inserted or deleted from a codon. Whereas point mutations, or substitutions, are a large category of mutations where the base, or nucleotide, is switched for another.

The genes these mutations often affect are known as tumour suppressor genes; alternately, they could turn normal proto-oncogenes into cancer-causing oncogenes. Tumour suppressors generally lead to cancer when they don’t work properly, as their main function is to slow down cell division and manage apoptosis - programmed cell death. Hence, when inactivated, the individual is at risk of developing cancer from uncontrolled cell division. In regards to cyclins, a mutation in the tumour suppressor gene known as p16, specifically a deletion, may prevent it from being able to inhibit cyclin D – dependent kinase activity [4].

Another common and important example of a tumour suppressor gene is TP53, which codes for the protein p53. A mutation in the TP53 gene - which is often even called the ‘guardian of the genome’ - can be fatal for cancer development. The p53 protein is involved in several significant central cellular processes, including but not limited to transcription, genomic stability, apoptosis, and DNA repair [5]. Structural mutations would result in the functional inactivation of p53. Under some circumstances, this can cause an immunity towards the DNA-damaging agents used in typical cancer treatment like chemotherapy and alternate radiotherapeutic approaches. Mutations in the p53 gene are generally what causes the growth and spread of cancer cells in the body. Functional inactivation is what has the most harmful effect in terms of cancer when dealing with tumour suppressor mutations.

On the contrary, oncogenes result from the activation of proto-oncogenes, concurrently causing cancer. The purpose of proto-oncogenes is to aid cell growth. However, when they mutate or too many copies are present, they become classified as oncogenes, which are consistently activated when they are not meant to be. These mutations are generally acquired and not inherited and are due to either chromosome rearrangements or gene duplication [6]. The epidermal growth factor receptor protein is a proto-oncogene that is involved in cell signalling pathways in control of both cell division and survival. The mutations that occur in the EGFR gene cause an increase in the number of proteins made on specific types of cancer cells. A number of different cancers are often associated with EGFR mutations, like breast cancer, glioblastoma, and more. Upon becoming an oncogene, the activation of EGFR leads to increased cell proliferation and cell growth (a trademark cancer cause) and decreased apoptosis [7]

Resisting apoptosis is one of the six main ‘hallmarks’ of cancer. The hallmarks of cancer outline the complexities of the development of cancer through organising them into six main ‘hallmarks’ [8]. These include sustaining proliferative signalling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting cell death (apoptosis). Apoptosis is a mechanism that programs a cell to die when damaged. This consequently helps an organism maintain its health by inhibiting the replication of these damaged cells. Cancer cells evade apoptosis through genetically altering the mechanisms detecting irregularities and preventing apoptosis activation as a result. There are multiple different pathways in which apoptosis may occur; for example, apoptosis induction through Death Receptors like Caspase-8 and RIP kinases is quite common [9]. Due to their gravity in the cell death induction process, death receptors like RIP kinases have been heavily studied. Its role has been specifically observed in liver cell death and inflammation, with studies showing that it has implications in the pathogenesis of liver disease due to its contribution to the regulation of caspase-dependent hepatocyte apoptosis induced by tumour necrosis factor (TNF) [10]. In a similar fashion, the impaired function and expression of Caspase-8 can initiate the formation of tumours and even cause some form of treatment resistance in certain types of cancers [11]. While these specific mutations lead to this hallmark of resisting cell death, other mutations bring about other equally important hallmarks in the development of cancer. 

Something that has been made consistently clear through discussions on the development of cancer is the huge role genetic mutations play. In some cancers, these mutations can be linked to factors other than just chance. Certain common risk factors include smoking, alcohol, and even communicable viruses [12]. Smoking is quite ordinarily understood to pose a risk to the development of cancer, specifically lung cancer. This is ascribable to the carcinogens found within cigarettes. A carcinogen is fundamentally a substance capable of causing cancer. Common carcinogens found in cigarettes are benzene and polycyclic aromatic hydrocarbons [13] Benzene is formed as a by-product of the combustion of tobacco in cigarettes, and its long-term effects include changes in the blood, for instance, it can cause bone marrow to produce less red blood cells. It is associated with a greatly increased risk of developing acute myeloid leukaemia. This proposition was confirmed in a study by researchers in the Department of Epidemiology, University of North Carolina, in which it was found that the benzene in cigarette smoke contributed from 8% to 48% of smoking-induced total leukaemia deaths [14]. Furthermore, smoking greatly increases the concentration of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in human lung tissue, due to tobacco smoke being the main source. These pollutants are highly toxic and mutagenic and are majorly concerning due to their ability to bind to cellular proteins and DNA. Such biochemical disruptions can cause mutations, tumours, and subsequently, cancer [15]. Studies have also confirmed a link to smoking – the sum of PAH concentrations was shown to be higher in smokers. Smoking even increased the concentration of five PAHs, like benzopyrene, which approximately increased by twofold [16].

Another risk factor, similar in terms of prevalence, would be oncoviruses, which can cause a cell to become cancerous due to its ability to insert its own DNA or RNA into its host cell. Their DNA is replicated and spreads, affecting the host cell’s genetic makeup on a large scale. Common viral infections that are known to be potentially cancer-causing are the human papillomavirus (HPV), and the hepatitis C virus (HCV). HPV can cause cancer as it combines its DNA with the host’s, hence disrupting regular cell function. However, viruses like HCV and human immunodeficiency virus (HIV) may simply increase the risk of cancer development due to their detrimental, weakening effect on a patient’s immune system [17] Whilst there is no treatment for HIV, there are preventative measures that can be taken to avoid contracting human papillomavirus, like a vaccine, and HCV is highly treatable despite there being no vaccine. Scientific knowledge surrounding oncoviruses like such allows for further research into treatment and clinical applications, which heavily underlines the importance of oncology and a general understanding of what goes wrong for cancers to develop. 

Vaccinations are a form of prevention rather than treatment, yet certain research into genetics and mutations can pave the path for cancer therapeutic strategies. For example, knowledge on the aforementioned p53 tumour suppressor gene is currently being utilised to identify molecular targets that chemotherapeutic, immunotherapeutic, and gene-therapeutic strategies can be based upon [5]. Similarly, upon extensive research, certain drugs have been found to block epidermal growth factor receptor proteins to prevent increased cell proliferation when EGFR is activated in excess. Targeting these proteins would be an effective approach to cancer treatment as they are part of important signalling pathways that lead to cell division. Epidermal growth factor receptors are a type of receptor tyrosine kinase, and developed strategies include using monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity. As a result, these prevent EGFR autophosphorylation; several anti-EGFR agents are being used in clinical development for cancer therapy [18]. 

To summarise, the question of what goes wrong for cancers to develop is not an easily answered one, and still requires a great deal of scientific research to be put forward. Whilst it has been widely accepted that gene mutations are the main cause of cancer, there are certain phenomena known as Carcinomas of unknown primary (CUP). This is a rare disease where malignant cells are found in the body, yet the location of where cancer began is unknown. This is a clear example of where oncology can be improved upon. However, the importance of some basic understanding of genetic mutations and alternate risk factors for the development of cancer is clearly beneficial to the progression of medicine and clinical advancement. Tumour suppressors and oncogenes form a general foreground for the comprehension of what it is that stimulates cancer development. With this knowledge, preventative measures can be taken to avoid prolonged exposure to a substance or activity that could potentially pose the risk of damaging a cell’s DNA. With a decreased pervasiveness of cancer, valuable time and money can be saved in hospitals. Relating back to the Sustainable Development Goals, this again works towards SDG 3: ‘Good Health and Well-being.’ Overall, what goes wrong for cancers to develop is a question with a multitude of answers, and the most significant thing that can be understood is the fact that there are several contributions with a similar weighting in terms of urgency and importance.

References

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