Minds on Medicine: Can Cancer be Combatted?
Cancer is a highly prevalent, multifaceted and unique disease that kills one in five individuals. Cancer cells arise from mutated human cells, so the diseased cells and tumours originate from our own bodies. Human cells turn into cancer cells in a process called oncogenic transformation requiring accumulated mutations, which may have genetic, infective, or environmental origins. A single mutation is not sufficient to change a normal cell into a cancer cell; the mutation of multiple genes in a single cell causes most cancers. The need for accumulation (often over time) explains why cancer incidence increases with age.
Cancer is a microevolutionary process, as a spontaneous mutation may give a single cell a selective advantage, allowing it to survive and divide more frequently than the surrounding cells. Repeated cycles of mutation, competition, and natural selection give rise to the onset of cancer: a disease in which an individual mutated cell survives and prospers at the expense of its neighbours. Most cancers derive from a single abnormal cell, which bypasses the normal proliferation (replication) controls, to invade and colonise territories typically reserved for other cells.
Hallmarks of cancer:
The ‘Hallmarks of Cancer’ were first proposed by Hanahan and Weinberg, in an attempt to reduce the complexity of cancer to a small number of underlying principles. When several of these traits accumulate, this marks the transformation of normal cells to malignant tumour cells. The updated version of the original paper includes eight hallmarks and two enabling characteristics:
Self sufficiency of growth signals or sustaining proliferative signalling: normal cells require signals from other cells in the organ to specify when they should grow and divide. Cancer cells do not require external signals to be stimulated to grow and reproduce, as they produce their own growth signals and have overactive signal receptors. This leads to the rapid proliferation of cancer cells, which results in tumour development.
Insensitivity to anti-growth signals or evading growth suppressors: most biological systems can inhibit excessive cell growth, in order to match consumption of resources to availability, but cancer cells ignore anti-growth signals and become resistant to them. This is often a result of a genetic mutation of tumour suppressor genes which are normally responsible for halting the cell division cycle.
Deregulation of cellular energetics and metabolism: normal cells follow step by step reactions along a standard metabolic pathway for the release of energy. By contrast, cancer cells use abnormal pathways, and the steps are irregular. Most tumours have a sugar metabolism more similar to that of a growing embryo than a normal adult tissue. Tumours can import glucose from the bloodstream at a rate up to 100 times faster than normal cells. This is used for energy, and also the production of raw materials like proteins, lipids and nucleic acids necessary to facilitate tumour growth.
Sustained or induced angiogenesis: tumours require a greater supply from the bloodstream to provide the increasing number of cells with enough oxygen and nutrients to sustain them. The cells give out signals to attract new blood vessels from the outside in a process called angiogenesis – the formation of new blood vessels from pre-existing vessels through the migration, growth, and differentiation of endothelial cells.
Evasion of the immune system: cancer cells can evade destruction by the body’s immune system defences which usually detect and remove foreign cells. The cells emit a ‘don’t eat me’ signal, which allows them to multiply and invade other tissues. Cancer immunotherapy is a developing field attempting to utilise the immune system to overcome this hallmark and destroy cancer cells.
Resistance to apoptosis: apoptosis is a biologically programmed cell death which is activated by cell damage. Mutations in tumour suppressor genes cause apoptosis signals to be disrupted, allowing cancer cells to avoid the normal cell death cycle and maintain tumour growth.
Infinite replication potential: normal cells have a built-in limit to the number of times they are able to divide and they permanently stop after a certain number of divisions, in a process known as replicative cell senescence. Growth without inhibition in cancer cells is a consequence of the activation of an enzyme called telomerase, which can maintain the small portion at the end of the chromosome, called a telomere, which is usually lost during cell division. The allows cancer cells to replicate indefinitely, as their telomeres do not shorten as they would in normal cell replication.
Metastasis: the process by which a benign tumour becomes malignant and cancer spreads to other sites in the body is known as metastasis. Cancerous cells travel through lymph nodes or in the bloodstream to migrate from the primary tumour site and establish a new tumour.
Inflammatory microenvironment: as tumours grow, the surrounding tissue becomes inflamed. This creates prime conditions for growth and angiogenesis, allowing the enhanced production of cancer cells within the microenvironment. This is an enabling characteristic for continued proliferation.
Genomic instability: changes to genes can either be mutations, deletion of whole genes, or the addition of extra copies. Changes to genes are enabling characteristics that disrupt control mechanisms, resulting in cells acquiring hallmark characteristics and transforming into cancer cells.
Cancer therapies:
Cancer therapies use a range of methods, and target a range of hallmarks, as each cancer is unique, and so responds best to a different treatment course. Local therapies (targeted to a specific area) include surgery to remove tumours, and radiotherapy. Systemic therapies act on the whole body, and often have more side-effects as a result. These include cytotoxic drugs (destructive to cells), hormonal therapies, or molecularly targeted therapies. Molecularly targeted therapies are administered systemically, but only act on targets, so do not affect all cells. These are often cytostatic, meaning they block tumour proliferation. Often multiple different types of therapy are used to treat a single cancer, and as treatments develop, more specialised personalised medicine is being used.
Genome projects and personalised medicine:
Personalised medicine is “therapy with the right drug at the right dose in the right patient”. This means that treatments are tailored to the unique type of cancer, and thus more likely to be effective than attempting a blanket treatment. Patients are separated into different groups, and the approach is chosen based on the unique variation of the human genome present in the specific cancer.
Cancer genome projects are important contributors to cancer research, as sequencing multiple cancer genomes may facilitate identification of all the mutations that contribute to tumour development. For example, the ‘BRAF V600E mutation’ has been found to be present in approximately 60% of malignant melanomas. As a result, a new treatment has been developed to target this using selective inhibitors. A BRAF inhibitor called Vemurafenib was developed, and induced responses in 77% of metastatic melanoma patients with the mutation. This is just one example of genome sequencing giving rise to new treatments, and this method is being applied to a range of known mutations to help develop the arsenal of treatments to be used in personalised medicine based on tumour genotype. Cancer is a complex complement of diseases, with each tumour presenting unique challenges, so the dream of a single ‘cure’ is not a practical one. However, genomic analysis, ongoing drug development, and the combination of a range of techniques in a personalised treatment plan, are all very promising ways to combat this destructive disease, allowing more and more cancers to be cured each day.
Featured Medicine Masterclass:
What is cancer? What are the current treatments used, and how can we look towards finding new cures?
Host: Rhiannon is currently studying for a MB ChB (Bachelor of Medicine and Surgery) at the University of Warwick, following an undergraduate degree in Experimental Psychology at the University of Oxford. At Oxford, Rhiannon’s excellent academic performance saw her receiving the Rank Prize Fund summer studentship, theProxime Accessit for the Weiskrantz Prize in Psychological Studies and the Domus Scholarship (Pembroke College, Oxford).
Duration: Suggested 1-2hrs, depending on the level of detail the student desires.