21.3: Hallmarks of Cancer - Biology

21.3: Hallmarks of Cancer - Biology

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Researchers have identified six molecular and cellular traits that characterize most cancers. In this chapter, we will focus on the first two hallmarks, namely growth signal autonomy and insensitivity to anti-­‐growth signals.

Table (PageIndex{1}) Ten Hallmarks of Cancer (Hanahan and Weinberg, 2000; Hanahan 2011)

1. Growth signal autonomy

Cancer cells can divide without the external signals normally required to stimulate division.

2. Insensitivity to growth inhibitory signals

Cancer cells are unaffected by external signals that inhibit division of normal cells.

3. Evasion of apoptosis

When excessive DNA damage and other abnormalities are detected, apoptosis (a type of programmed cell death) is induced in normal cells, but not in cancer cells.

4. Reproductive potential not limited by telomeres

Each division of a normal cell reduces the length of its telomeres. Normal cells arrest further division once telomeres reach a certain length. Cancer cells avoid this arrest and/or maintain the length of their telomeres.

5. Sustained angiogenesis

Most cancers require the growth of new blood vessels into the tumor. Normal angiogenesis is regulated by both inhibitory and stimulatory signals not required in cancer cells.

6. Tissue invasion and metastasis

Normal cells generally do not migrate (except in embryo development). Cancer cells invade other tissues including vital organs.

7. Deregulated metabolic pathways

Cancer cells use an abnormal metabolism to satisfy a high demand for energy and nutrients.

8. Evasion of the immune system

Cancer cells are able to evade the immune system.

9. Chromosomal instability

Severe chromosomal abnormalities are found in most cancers.

10. Inflammation

Local chronic inflammation is associated with many types of cancer.

21.3: Hallmarks of Cancer - Biology

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Reviewer(s)' Comments to Author:

Comments to the Author(s)
A significant and well-researched review that promises to be of interest to a wide audience.Suggestions below are to improve clarity:
Abstract lists non-genetic changes that affect gene expression but throughout the manuscript this is referred to as Epigenetic dysregulation so I suggesting changing this in the abstract.
Two components of Figure 2(not a feature among normal cells and chronic manner) is not mentioned in supporting text.
Page7- should read:non-cancer cells to acquire stem cell-like features.
Page 16- Sustained proliferative signalling needs a number. Some of the hallmarks under epigenetics have a clear mechanism (ie oncometabolites interferring with enzyme activity/mutation) but some others do not.May add.
P22- Recommend deleting "The protective effects against asthma are due to. " not relevant to this article.
Figure 9- I would illiustrate tumors occurring in the Crypts (not on villi)
p27-epigenetic factors such as diet- this should be mentioned earlier in the paper
p28- text under Fig 10- it may be helpful to link discussion to the gut as in Figure 10
p29 We need to consider more than simply bacteria and viruses--but then talks about viruses- possible move this the paragraph on fungus?
p32 2nd paragraph- remove (in response to stress) and 3rd paragrph add beter2 adrenergic receptor ON ENDOTHELIAL CELLs
p39 Delete "even better pain management-NOT discussed. Delete (interact with the microenvironment) And add " We consider two ADDITIONAL core hallmarks.
One possible but strictly optional additional hallmark to consider may be inter-cellular communication (via exosomes)

Comments to the Author(s)
This is a timely update of Hanahan and Weinberg's “Hallmarks of Cancer”. The review is extremely well researched and for each new Hallmark, multiple examples are provided. Most importantly, though, the article provides a conceptual framework for thinking about targeting each new Hallmark. The figures are beautiful. I can see this as becoming required reading in Cancer Biology courses worldwide. I wouldn't change a thing.

Hallmarks of Cancer 3: Evading Apoptosis

The Hallmarks of Cancer are ten underlying principles shared by all cancers. The first and second Hallmark of Cancer articles can be found here and here.

The Hallmarks of Cancer are ten underlying principles shared by all cancers. The first and second Hallmark of Cancer articles can be found here and here.

The Third Hallmark of Cancer is defined as "Evading Apoptosis". Apoptosis is the opposite of cell growth it is cell death. To divide and grow uncontrollably, a cancer cell not only has to hijack normal cellular growth pathways, but also evade cellular death pathways. Indeed, this acquired resistance to apoptosis is characteristic of all types of cancer. But before I explain how cancer cells do this, we need to understand how the process of cellular death occurs in a normal cell.

The apoptotic program is hardwired into every single cell in our body. It is like a cyanide capsule, swiftly delivering death if the circumstances require cellular suicide. If a cell detects that it has damaged DNA, it can activate apoptosis to remove itself from the population. Apoptosis, or cellular suicide, is an entirely normal function of cells. The same apoptotic program is activated when a tadpole changes into a frog the cells in the tail die through apoptosis, and the tail disappears. The same is true for the webbing between our fingers in our early embryonic development. Apoptosis is an extremely tidy process cellular membranes are disrupted, the chromosomes are degraded, the DNA breaks up into fragments, and the dying, shrinking cell is swallowed up by a neighboring cell or a patrolling immune cell, leaving no trace of the cellular suicide behind.

Regulators and Effectors

So how does apoptosis work at the molecular level? The apoptotic machinery can be divided into two broad categories regulators and effectors. The regulators are responsible for monitoring the interior and exterior environment of the cell for conditions of abnormality in order to decide whether that cell should live or die. The possible abnormalities include DNA damage, signaling imbalance caused by the activation of cancer causing genes (oncogenes), lack of an oxygen supply or insufficient growth factors.

Apoptosis can therefore occur either through an intrinsic pathway, in which signals from within the cell activate the process, or through an extrinsic pathway where death signals from outside the cell are received and processed by the cell to activate apoptosis. It is thought that the intrinsic apoptotic pathway is more important in cancer prevention than the extrinsic pathway. Given how our cells carry machinery to destroy themselves with the precision of an executioner, it comes as no surprise that the process is tightly regulated.

The primary regulators of apoptosis are proteins belonging to a group known as the Bcl-2 family. These proteins can either be pro-apoptotic or anti-apoptotic Bcl-2, Bcl-XL, Bcl-W, Mcl-1 and A1 proteins function as anti-apoptotic proteins that inhibit apoptosis, while Bax, Bad, Bid, Bok, Bik and Bak (I swear these names are not made up!*) are pro-apoptotic proteins that trigger apoptosis when activated. The anti-apoptotic proteins bind to and inactivate the pro-apoptotic proteins in a healthy cell that does not need to die. Apoptosis regulators also include death receptors on the cell surface which bind to death signaling molecules, as part of the extrinsic apoptotic pathway. This is similar to the way growth factors bind to and activate growth factor receptors, as I described previously, and this binding triggers the effectors of apoptosis.

The Suicide Machines

Where is Mission Control for apoptosis? Many of the apoptotic signaling pathways converge at the mitochondria. Mitochondria are tiny organelles floating within a cell, and function as the cell's energy factories. They contain a signaling molecule known as cytochrome c, which is bound to the mitochondrial membrane. In response to pro-apoptotic signals (from pro-apoptotic proteins such as Bax), cytochrome c is released into the cell by the mitochondria, and they bind to a protein known as Apaf-1. This results in the formation of the apoptosome. The apoptosome is an extremely beautiful structure resembling a wheel with seven spokes. Once formed, the apoptosome goes on to activate a group of proteins known as caspases.

All our cells contain the seeds of their own destruction these come in the form of caspases. Caspases can be thought of as cellular executioners. They are proteins that degrade other proteins in our cells. Active caspases can wreak havoc within a cell and are therefore extremely dangerous, so they are produced in an inactive form by the cell (known as pro-caspases), like an executioner's blade that is sheathed. Upon detecting an increase in the amount of cytochrome c, released from the mitochondria, the blades are unsheathed. There are 13 such caspase genes identified in the human genome so far. Two of the caspase proteins act as 'gatekeeper' caspases: caspase-8 and caspase-9. They are initiator caspases that, when activated by cytochrome c release, go on to activate the other caspases in a cascade of irreversible cellular protein degradation.

P53: The Guardian of the Genome

How do cells detect the necessary conditions for triggering apoptosis? In the previous Hallmark of Cancer article, I explained the fundamental role of the Retinoblastoma protein in controlling cell division. Retinoblastoma, remember, is a vitally important brake on cell division. Damage to a cell's Retinoblastoma gene releases this brake, leading to uncontrolled cell growth.

Similarly, P53 is an extremely important protein, dubbed 'The Guardian of the Genome'. Amongst its many functions, it is responsible for detecting DNA damage, chromosome abnormalities and arresting the cell cycle to initiate repair if repair is not possible then apoptosis is induced. P53 induces apoptosis by increasing the production of the pro-apoptotic protein Bax. Bax stimulates the mitochondria to release cytochrome c, which activates the caspase cascade which ultimately results in cell suicide. P53 is vital for maintaining the integrity of our genome at the most fundamental level.

Evading apoptosis

So how do cancer cells escape death? The most common method is the loss of the apoptosis gatekeeper, the protein P53. More than half of all types of human cancers have a mutated or missing gene for p53, resulting in a damaged or missing P53 protein. As an alternative to achieving the loss of P53, cancer cells can compromise the activity of P53 by increasing the inhibitors of P53, or silencing the activators of P53. Previously I explained how the human papillomavirus produces a protein known as E7, which binds to and inactivates Retinoblastoma.

Similarly, another protein, E6, also produced by the human papilloma virus, binds to and inactivates P53. These two cancer-causing proteins, E6 and E7 (oncoproteins), therefore disable two vital gatekeepers, Retinoblastoma and P53, that control both cell division and cell death the result is repeated uncontrolled cell division that manifests itself in warts, with strong associations with the development of cancer. Cancer cells can also produce excessive amounts of anti-apoptotic proteins such as Bcl-2, Bcl-XL etc. They can produce less of the pro-apoptotic proteins such as Bax and Bak. They can short-circuit the extrinsic death receptor apoptotic pathway.

It comes as no surprise that highly aggressive cancers often have both Retinoblastoma and P53 mutations. As a result, these rapidly growing tumors have extremely low levels of apoptosis and extremely high levels of cell division. Like de-rigging the Sword of Damocles, cancer cells can inactivate the machineries of death and the evasion of apoptosis by cancer cells therefore represents a key breach of an extremely important anti-cancer defense mechanism.

Next time…”Limitless Replicative Potential ”

*in case you were curious, the pro-apoptotic members of the Bcl-2 family are thus named:

Bax: Bcl-2 Associated X protein

Bad: Bcl-2 Associated Death promoter

Bid: BH3 interacting-domain Death agonist

Bok: Bcl-2 related Ovarian Killer

Bik: Bcl-2 Interacting Killer

Bak: Bcl-2 homologous Antagonist Killer

The views expressed are those of the author(s) and are not necessarily those of Scientific American.

The Hallmarks of Cancer

The hallmarks of cancer comprise eight characteristics which are thought of as the defining features of cancer. They are physiological alterations which are acquired during tumour development to overcome anti-cancer mechanisms and it is suggested that these characteristics are shared by most, if not all tumour types.

In 2000, Hanahan and Weinberg proposed the original six hallmarks:

Self-sufficiency in growth signals

Insensitivity to anti-growth signals

Limitless replicative potential

Tissue invasion and metastasis

And then they later added two more in 2011:

Avoiding immune destruction

Reprogramming of energy metabolism

What is a Tumour?

Tumours are more than just a mass of cancerous cells they are in fact complex tissues made up of multiple different cell types. As well as cancer stem cells which have the ability to self-renew and maintain the tumour, tumours also contain immune cells, endothelial cells and fibroblasts. These cells interact together to influence the development and progression of cancer by expressing these hallmark capabilities.

So, what do these hallmarks actually mean?

1.Self-sufficiency in growth signals

Normal cells need signals to enable them to enter a proliferative state, but tumour cells are able to produce their own signals enabling them to continue through the cell cycle to proliferate

2. Insensitivity to anti-growth signals

In normal cells antiproliferative signals block the growth and division of cells, forcing them into a dormant state known as quiescence. In cancer however, cells are insensitive to these anti-growth signals and are able to progress through the cell cycle allowing uncontrolled cell division

3. Evading apoptosis

Apoptosis, also known as programmed cell death, is a process which removes unwanted and potentially dangerous cells from our body including potential tumour cells. If cancer cells are to develop into a tumour, they require the ability to avoid death in order to grow and proliferate

4. Limitless reproduction potential

This essentially means the cancer cells become immortal, or close enough. In the perfect conditions they have the limitless potential to grow and divide, allowing them to maintain the population of cancer stem cells.

5. Sustained angiogenesis

Angiogenesis is the creation of new blood vessels from pre-existing ones, a process that rarely occurs in adults. In cancer it is a fundamental step for tumours to transition from benign to malignant as they need a greater supply of oxygen and nutrients to survive and continue growing

6. Tissue invasion and metastases

Primary tumours can migrate from their site of origin and produce a secondary tumour at another site, also known as metastases, a process responsible for most cancer-related deaths

7. Reprogramming of energy metabolism

Cancer cells don’t use normal metabolic pathways such as oxidative phosphorylation to make energy, instead they produce ATP through the process of glycolysis

8. Evading immune destruction

The immune system will destroy most cancer cells, as it usually does with foreign bodies. Some cancer cells may be able to avoid this by picking up mutations enabling them to evade immune destruction

How are these important in developing targeted therapies?

The hallmarks of cancer are key to a greater understanding of tumour biology and cancer biology as a whole. Already many of the treatments that have been developed are directed towards these specific molecular targets involved in enabling the progression of cancer. However, in response to therapy cancer cells can reduce their dependence on a particular hallmark, enabling a form of acquired drug resistance. A challenge that will hopefully soon be overcome by current advancements in cancer treatment and therapies.

About Sophie:

Currently studying a Masters in Molecular Medicine at the University of Leeds. I’m usually found with a coffee in hand and either trying to stay on top of deadlines or snapping pics of my food for instagram (yes I’m one of THOSE people!)

Swiss Institute for Experimental Cancer Research, Department of Molecular Oncology, Swiss Federal Institute of Technology, Lausanne, Switzerland

Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA, USA

Swiss Institute for Experimental Cancer Research, Department of Molecular Oncology, Swiss Federal Institute of Technology, Lausanne, Switzerland

Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA, USA


An enigma for cancer medicine lies in its complexity and variability, at all levels of consideration. The hallmarks of cancer constitute an organizing principle that provides a conceptual basis for distilling the complexity of this disease in order to better understand it in its diverse presentations. This conceptualization involves eight biological capabilities—the hallmarks of cancer—acquired by cancer cells during the long process of tumor development and malignant progression. Two characteristic traits of cancer cells facilitate the acquisition of these functional capabilities. The eight distinct hallmarks consist of sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, deregulating cellular energetics and metabolism, and avoiding immune destruction. The principal facilitators of their acquisition are genome instability with consequent gene mutation and tumor-promoting inflammation. The integration of these hallmark capabilities involves heterotypic interactions among multiple cell types populating the “tumor microenvironment” (TME), which is composed of cancer cells and a tumor-associated stroma, including three prominent classes of recruited support cells—angiogenic vascular cells (AVC), various subtypes of fibroblasts, and infiltrating immune cells (IIC). In addition, the neoplastic cells populating individual tumors are themselves typically heterogeneous, in that cancer cells can assume a variety of distinctive phenotypic states and undergo genetic diversification during tumor progression. Accordingly, the hallmarks of cancer—this set of necessarily acquired capabilities and their facilitators—constitute a useful heuristic tool for elucidating mechanistic bases and commonalties underlying the pathogenesis of diverse forms of human cancer, with potential applications to cancer therapy.

Loss of Proteostasis

Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis (Powers et al., 2009) ( Figure 3 ). All cells take advantage of an array of quality control mechanisms to preserve the stability and functionality of their proteomes. Proteostasis involves mechanisms for the stabilization of correctly folded proteins, most prominently the heat-shock family of proteins, and mechanisms for the degradation of proteins by the proteasome or the lysosome (Hartl et al., 2011 Koga et al., 2011 Mizushima et al., 2008). Moreover, there are regulators of age-related proteotoxicity, such as MOAG-4, that act through an alternative pathway distinct from molecular chaperones and proteases (van Ham et al., 2010). All these systems function in a coordinated fashion to restore the structure of misfolded polypeptides or to remove and degrade them completely, thus preventing the accumulation of damaged components and assuring the continuous renewal of intracellular proteins. Accordingly, many studies have demonstrated that proteostasis is altered with aging (Koga et al., 2011). Additionally, chronic expression of unfolded, misfolded or aggregated proteins contributes to the development of some age-related pathologies, such as Alzheimer’s disease, Parkinson’s disease and cataracts (Powers et al., 2009).

Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock proteins (HSP) or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. The autophagic pathways include recognition of unfolded proteins by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated autophagy) or sequestration of damaged proteins and organelles in autophagosomes that later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects.

Chaperone-mediated protein folding and stability

The stress-induced synthesis of cytosolic and organelle-specific chaperones is significantly impaired in aging (Calderwood et al., 2009). A number of animal models support a causative impact of chaperone decline on longevity. In particular, transgenic worms and flies overexpressing chaperones are long-lived (Morrow et al., 2004 Walker and Lithgow, 2003). Also, mutant mice deficient in a co-chaperone of the heat-shock family exhibit accelerated-aging phenotypes, whereas long-lived mouse strains show a marked up-regulation of some heat-shock proteins (Min et al., 2008 Swindell et al., 2009). Moreover, activation of the master regulator of the heat-shock response, the transcription factor HSF-1, increases longevity and thermotolerance in nematodes (Chiang et al., 2012 Hsu et al., 2003), while amyloid-binding components can maintain proteostasis during aging and extend lifespan (Alavez et al., 2011). In mammalian cells, deacetylation of HSF-1 by SIRT1 potentiates the transactivation of heat-shock genes such as Hsp70, whereas down-regulation of SIRT1 attenuates the heat-shock response (Westerheide et al., 2009).

Several approaches for maintaining or enhancing proteostasis aim at activating protein folding and stability mediated by chaperones. Pharmacological induction of the heat-shock protein Hsp72 preserves muscle function and delays progression of dystrophic pathology in mouse models of muscular dystrophy (Gehrig et al., 2012). Small molecules may be also employed as pharmacological chaperones to assure the refolding of damaged proteins and to improve age-related phenotypes in model organisms (Calamini et al., 2012).

Proteolytic systems

The activities of the two principal proteolytic systems implicated in protein quality control, namely, the autophagy-lysosomal system and the ubiquitin-proteasome system, decline with aging (Rubinsztein et al., 2011 Tomaru et al., 2012), supporting the idea that collapsing proteostasis constitutes a common feature of old age.

Regarding autophagy, transgenic mice with an extra copy of the chaperone-mediated autophagy receptor LAMP2a do not experience aging-associated decline in autophagic activity and preserve improved hepatic function with aging (Zhang and Cuervo, 2008). Interventions using chemical inducers of macroautophagy (another type of autophagy different from chaperone-mediated autophagy) have spurred extraordinary interest after the discovery that constant or intermittent administration of the mTOR inhibitor rapamycin can increase the lifespan of middle-aged mice (Blagosklonny, 2011 Harrison et al., 2009). Notably, rapamycin delays multiple aspects of aging in mice (Wilkinson et al., 2012). The lifespan-extending effect of rapamycin is strictly dependent on the induction of autophagy in yeast, nematodes and flies (Bjedov et al., 2010 Rubinsztein et al., 2011). However, similar evidence does not exist yet for the effects of rapamycin on mammalian aging, and other mechanisms such as inhibition of the ribosomal S6 protein kinase 1 (S6K1) implicated in protein synthesis (Selman et al., 2009), could contribute to explain the pro-longevity effects of rapamycin (see section on Deregulated Nutrient-sensing). Spermidine, another macroautophagy inducer that, in contrast to rapamycin, has no immunosuppressive side-effects, also promotes longevity in yeast, flies and worms via the induction of autophagy (Eisenberg et al., 2009). Similarly, nutrient supplementation with polyamine preparations containing spermidine or provision of a polyamine-producing gut flora increases longevity in mice (Matsumoto et al., 2011 Soda et al., 2009). Dietary supplementation with ω-6 polyunsaturated fatty acids also extends lifespan in nematodes through autophagy activation (O’Rourke et al., 2013).

In relation to the proteasome, activation of EGF-signaling extends longevity in nematodes by increasing the expression of various components of the ubiquitin-proteasome system (Liu et al., 2011a). Likewise, the enhancement of proteasome activity by deubiquitylase inhibitors or proteasome activators accelerates the clearance of toxic proteins in human cultured cells (Lee et al., 2010), and extends replicative lifespan in yeast (Kruegel et al., 2011). Moreover, increased expression of the proteasome subunit RPN-6 by the FOXO transcription factor DAF-16 confers proteotoxic stress resistance and extends lifespan in C. elegans (Vilchez et al., 2012).


There is evidence that aging is associated with perturbed proteostasis, and experimental perturbation of proteostasis can precipitate age-associated pathologies. There are also promising examples of genetic manipulations that improve proteostasis and delay aging in mammals (Zhang and Cuervo, 2008).

The Ten Hallmarks of Cancer

In 2002, Robert Weinberg and Douglas Hanahan published a review article in the journal Cell titled “The Hallmarks of Cancer”. It was a seminal paper in every sense of the word downloaded 20,000 times a year between 2004 and 2007, with over 15,000 citations in other research papers.

Why is this paper so important? Cancer, as we know by now, is an incredibly complicated disease. Weinberg and Hanahan simplified it to six underlying principles. The hugely complex beast that is cancer, so diverse that even the same organ can have many different tumor types, was reduced to just six common traits that every single cancer shares, to facilitate that transformation from a normal cell to a cancer cell. It answers the ‘how does cancer happen’ question very elegantly, and we gain insight into all the different things that go wrong in a cancer cell.

In 2011, Weinberg and Hanahan updated their list by proposing four more new Hallmarks of Cancer, in another Cell paper titled “The Hallmarks of Cancer: The Next Generation”.

Over the coming weeks, I will go through each of these hallmarks in detail, explaining the processes behind each one. By demystifying what cancer is, and how it arises, I hope in some way to alleviate the terror that this word can inspire a ‘know thy enemy’ of sorts, if you will. I will also be around, as always, to answer any questions that come up during the discussion. I will also update this article, and use it as a ‘landing page’ with links to each new article of the series as I publish it on Australian Science.

The gorgeous image below is a composite from a time-lapse of a HeLa cell (cervical cancer) undergoing cell division. Cellular structures have been visualized using cyan (cell membrane) and red (DNA).

Composite from a time-lapse of a HeLa cell (cervical cancer) undergoing cell division. Cellular structures have been visualized using cyan (cell membrane) and red (DNA). Image Credit: Kuan-Chung Su, London Research Institute, Cancer Research UK, Wellcome Images

21.3: Hallmarks of Cancer - Biology

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list—reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.


Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis).

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 (apoptosis). 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 (mutations that are not inherited but occur after conception). 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 Edit

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 (negative feedback). 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. [4] [5]

Insensitivity to anti-growth signals Edit

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 (when the DNA is damaged, for example). 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. [4] [6]

Evading programmed cell death Edit

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. [4] [7]

Limitless replicative potential Edit

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 (senescence), or die (crisis). 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 (telomerase) to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence. [4] [8]

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 (10 −7 ) 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 (loses nucleotides at the ends of chromosomes) 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. [9]

Sustained angiogenesis Edit

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. [4] [10]

Tissue invasion and metastasis Edit

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. [4] [11]

In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation." [2]

Emerging Hallmarks Edit

Deregulated metabolism Edit

Most cancer cells use alternative metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, [12] [13] but only now gaining renewed research interest. [14] Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration (oxidation of pyruvate, the citric acid cycle, and the electron transport chain). 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 (PTP) from triggering of apoptosis. [15] [16]

The ketogenic diet is being investigated as an adjuvant therapy for some cancers, [17] [18] [19] including glioma, [20] [21] because of cancer's inefficiency in metabolizing ketone bodies.

Evading the immune system Edit

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. (See cancer immunology)

Enabling Characteristics Edit

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 Edit

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 (rather than the normal diploid number of 46). [22] Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates. (See genome instability)

Inflammation Edit

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. (See inflammation in cancer)

An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. [23] The only hallmark of malignant disease was its ability to invade and metastasize. [23]

An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. [24] It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading.