The Hallmarks of Cancer
"The Hallmarks of Cancer" is a seminal peer-reviewed article published in the journal Cell in January 2000 by the cancer researchers Douglas Hanahan and Robert Weinberg.
The authors believe that the complexity of cancer can be reduced to a small number of underlying principles. The paper argues that all cancers share six common traits that govern the transformation of normal cells to cancer cells.
The traits that the authors highlight in the paper are Cancer cells stimulate their own growth ; They resist inhibitory signals that might otherwise stop their growth ; They resist their programmed cell death ; They can multiply indefinitely They stimulate the growth of blood vessels to supply nutrients to tumors ; They invade local tissue and spread to distant sites.
By November 2010, the paper had been referenced over 15,000 times by other research papers, and was downloaded 20,000 times a year between 2004 and 2007. As of March 2011, it was Cell's most cited article.
In an update published in 2011, Weinberg and Hanahan proposed two new hallmarks: abnormal metabolic pathways and evading the immune system, and two enabling characteristics: genome instability, and inflammation.
List of hallmarks
Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms.Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit programmed cell death. They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.
All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical protein must malfunction in each of those mechanisms. These proteins become non-functional or malfunctioning when the DNA sequence of their genes is damaged through acquired or somatic mutations. This occurs in a series of steps, which Hanahan and Weinberg refer to as hallmarks.
| Capability | Simple analogy |
| Self-sufficiency in growth signals | "accelerator pedal stuck on" |
| Insensitivity to anti-growth signals | "brakes don't work" |
| Evading apoptosis | won't die when the body normally would kill the defective cell |
| Limitless replicative potential | infinite generations of descendants |
| Sustained angiogenesis | telling the body to give it a blood supply |
| Tissue invasion and metastasis | migrating and spreading to other organs and tissues |
Self-sufficiency in growth signals
Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signalling; by permanently activating the signalling pathways that respond to these signals; or by destroying 'off switches' that prevents excessive growth from these signals. In addition, cell division in normal, non-cancerous cells is tightly controlled. In cancer cells, these processes are deregulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor.Insensitivity to anti-growth signals
To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are orchestrated by proteins known as tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not. In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division, even when the cell has severe abnormalities. Another way cells prevent over-division is that normal cells will also stop dividing when the cells fill up the space they are in and touch other cells; known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings.Evading programmed cell death
Cells have the ability to 'self-destruct'; a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability; even though cells may become grossly abnormal, they do not undergo apoptosis. The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. This means that proper signaling cannot occur, thus apoptosis cannot activate. They may also have defects in the downstream signaling itself, or the proteins involved in apoptosis, each of which will also prevent proper apoptosis.Limitless replicative potential
Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide, or die. The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence.Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60–70 doublings, at which point they reach a stage of senescence.
This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.
The counting device for cell doublings is the telomere, which decreases in size during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres.
Sustained angiogenesis
Normal tissues of the body have blood vessels running through them that deliver oxygen from the lungs. Cells must be close to the blood vessels to get enough oxygen for them to survive. New blood vessels are formed during the development of embryos, during wound repair and during the female reproductive cycle. An expanding tumour requires new blood vessels to deliver adequate oxygen to the cancer cells, and thus exploits these normal physiological processes for its benefit. To do this, the cancer cells acquire the ability to orchestrate production of new vasculature by activating the 'angiogenic switch'. In doing so, they control non-cancerous cells that are present in the tumor that can form blood vessels by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote blood vessel formation.Tissue invasion and metastasis
One of the most well known properties of cancer cells is their ability to invade neighboring tissues. It is what dictates whether the tumor is benign or malignant, and is the property which enables their dissemination around the body. The cancer cells have to undergo a multitude of changes in order for them to acquire the ability to metastasize, in a multistep process that starts with local invasion of the cells into the surrounding tissues. They then have to invade blood vessels, survive in the harsh environment of the circulatory system, exit this system and then start dividing in the new tissue.Updates
In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two emerging characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation."Emerging Hallmarks
Deregulated metabolism
Most cancer cells use abnormal metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, but only now gaining renewed research interest. Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration. Instead of completely oxidizing glucose to produce as much ATP as possible, cancer cells would rather convert pyruvate into the building blocks for more cells. In fact, the low ATP:ADP ratio caused by this effect likely contributes to the deactivation of mitochondria. Mitochondrial membrane potential is hyperpolarized to prevent voltage-sensitive permeability transition pores from triggering of apoptosis.The ketogenic diet is being investigated as an adjuvant therapy for some cancers, including glioma, because of cancer's inefficiency in metabolizing ketone bodies.
Evading the immune system
Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33 immune system.Enabling Characteristics
The updated paper also identified two emerging characteristics. These are labeled as such since their acquisition leads to the development of the hypothesized "hallmarks"Genome instability
Cancer cells generally have severe chromosomal abnormalities which worsen as the disease progresses. HeLa cells, for example, are extremely prolific and have tetraploidy 12, trisomy 6, 8, and 17, and a modal chromosome number of 82. Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge cycle, they are able to mutate at much faster rates.Inflammation
Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer. Inflammation leads to angiogenesis and more of an immune response. The degradation of extracellular matrix necessary to form new blood vessels increases the odds of metastasis.Criticisms
An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. The only hallmark of malignant disease was its ability to invade and metastasize.An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading.