The Hallmarks of Cancer

"The Hallmarks of Cancer"[1] is a seminal[2][3] 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
("hallmarks") that govern the transformation of normal cells to cancer (malignant or
tumor) cells.

The traits ("hallmarks") that the authors highlight in the paper are (1) Cancer cells The ability to invade surrounding
stimulate their own growth (self-sufficiency in growth signals); (2) They resist tissue and metastasise is a hallmark
inhibitory signals that might otherwise stop their growth (insensitivity to anti-growth of cancer.
signals); (3) They resist their programmed cell death (evading apoptosis); (4) They
can multiply indefinitely (limitless replicative potential) (5) They stimulate the
growth of blood vessels to supply nutrients to tumors sustained
( angiogenesis); (6) They invade local tissue and spread to distant sites
(tissue invasion and metastasis).

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.[4] As of March 2011, it was Cell's most cited article.[2]

In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed four new hallmarks:
, and (4) inflammation.[5]
(1) abnormal metabolic pathways, (2) evading the immune system, (3) genome instability

Contents
List of hallmarks
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Evading programmed cell death
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis
Updates
Deregulated metabolism
Evading the immune system
Genome instability
Inflammation
Criticisms
Notes and references
Bibliography

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 (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. Signalling pathways are deregulated
in cancer. Hanahan and Weinberg
All these mechanisms must be overcome in order for a cell to develop into a cancer. compared the signalling pathways to
electronic circuits where transistors
Each mechanism is controlled by several proteins. A critical protein must
are replaced by proteins. The
malfunction in each of those mechanisms. These proteins become non-functional or
prototypical Ras pathway starts with
malfunctioning when the DNA sequence of their genes is damaged through acquired an extracellular signal from growth
or somatic mutations (mutations that are not inherited but occur after conception). factors (such as TGF-α). Other major
This occurs in a series of steps, which Hanahan and W
einberg refer to as hallmarks. extracellular signals are anti-growth
factors (such as TGF-β), death
Summary factors (such as FASL), cytokines
(such as IL-3/6)and survival factors
Capability Simple analogy
(such as IGF1). Proteins inside the
Self-sufficiency in growth cell control the cell cycle, monitor for
"accelerator pedal stuck on"
signals DNA damage and other
Insensitivity to anti- abnormalities, and trigger cell suicide
"brakes don't work"
growth signals (apoptosis). Hanahan and
Weinberg's signal pathway
won't die when the body normally would kill
Evading apoptosis illustration is at Cell 100:59[6]
the defective cell
Limitless replicative
infinite generations of descendants
potential
Sustained angiogenesis telling the body to give it a blood supply
Tissue invasion and migrating and spreading to other organs and
metastasis tissues

Self-sufficiency in growth signals

Cancer cells do not need stimulation from external signals (in the form of growth factors) to
multiply.

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
.[7][8]
control them are altered, leading to increased growth and cell division within the tumor

Insensitivity to anti-growth signals

Cancer cells are generally resistant to growth-preventing signals from their neighbours.
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.[7][9]

Evading programmed cell death The cell cycle clock. Cells do not
divide in G0 and are quiescent. After
Apoptosis is a form of programmed cell death (cell receiving growth factor signals, they
suicide), the mechanism by which cells are programmed prepare for division by entering G1,
to die in the event they become damaged. Cancer cells where everything within the cell
are characteristically able to bypass this mechanism. except DNA is doubled. This
doubling includes the size of the cell.
Cells have the ability to 'self-destruct'; a process known as apoptosis. This is The next phase of the cell cycle is S
(synthesis) phase. It is the cell cycle
required for organisms to grow and develop properly, for maintaining tissues of the
phase where the chromosomes
body, and is also initiated when a cell is damaged or infected. Cancer cells, however,
(DNA) are duplicated in preparation
lose this ability; even though cells may become grossly abnormal, they do not for cellular division. The transition
apoptose. The cancer cells may do this by altering the mechanisms that detect the from G1 to S is a checkpoint. If the
damage or abnormalities. This means that proper signalling cannot occur, thus cell has damaged DNA or is
apoptosis cannot activate. They may also have defects in the downstream signalling expressing oncogenes or other
inappropriate proteins, specialized
itself, or the proteins involved in apoptosis, each of which will also prevent proper
checkpoint proteins, tumor
apoptosis.[7][10]
suppressors such as p53 or pRB, will
interrupt the transition to S phase
until the damage is repaired. If the
Limitless replicative potential damage cannot be repaired, the cell
will initiate apoptosis, often referred
Non-cancer cells die after a certain number of divisions. to as cellular suicide, which is
Cancer cells escape this limit and are apparently programmed cell death. If the tumor
capable of indefinite growth and division (immortality). suppressor genes incur loss-of-
But those immortal cells have damaged chromosomes, function mutations or are knocked
which can become cancerous. out, the damaged cell can continue
to divide unchecked — one of the
Cells of the body don't normally have the ability to divide indefinitely. They have a hallmarks of cancer.
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 that increase the length of
, without initiating senescence.[7][11]
telomeres. Thus, they can divide indefinitely

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
The hallmarks of cancer.
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.[12]

Sustained angiogenesis

Angiogenesis is the process by which new blood vessels are formed. Cancer cells appear to
be able to kickstart this process, ensuring that such cells receive a continual supply of
oxygen and other nutrients.

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
[7][13]
production, and increasing the production of factors that promote blood vessel formation.

Tissue invasion and metastasis

Cancer cells can break away from their site or organ of origin to invade surrounding tissue
and spread (metastasize) to distant body parts.

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 reason for 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. It is 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
[7][14]
this system and then start dividing in the new tissue.

Updates
In his 2010 NCRI conference talk, Hanahan proposed four new hallmarks. These were later codified in an updated review article
[5]
entitled "Hallmarks of cancer: the next generation."

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,[15] but only now gaining renewed research interest.[16] 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 preventvoltage-sensitive permeability transition pores(PTP) from triggering ofapoptosis.[17][18]

The ketogenic diet is being investigated as an adjuvant therapy for some cancers,[19][20] including glioma,[21] because of cancer’s
inefficiency in metabolizingketone 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 via a loss of interleukin-33immune system. (See cancer immunology)

Genome instability
Cancer cells generally have severe chromosomal abnormalitieswhich 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. (Seegenome instability)

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. (Seeinflammation in cancer)

Criticisms
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 andmetastasize.[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.

Notes and references

1. Hanahan D, Weinberg RA (January 2000). "The Hallmarks of Cancer".Cell. 100 (1): 57–70. doi:10.1016/S0092-
8674(00)81683-9 (https://doi.org/10.1016/S0092-8674%2800%2981683-9) . PMID 10647931 (https://www.ncbi.nlm.ni
h.gov/pubmed/10647931).
2. "Scientists Revisit 'Hallmarks of Cancer'" (https://www.sciencedaily.com/releases/2011/03/110316113057.htm).
Science Daily. 16 March 2011. Retrieved 2011-04-04.
3. "The Hallmarks of Cancer"(http://www.thenakedscientists.com/HTML/content/interviews/interview/1476/). Science
Interviews. November 2010. Retrieved 2011-04-04.
4. Hallmarks of Cancer, Cancer Research UK Science Update blog, November 2010(http://scienceblog.cancerresearc
huk.org/2010/11/10/ncri-conference-the-hallmarks-of-cancer/)
5. Hanahan, D.; Weinberg, R. A. (2011). "Hallmarks of Cancer: The Next Generation".Cell. 144 (5): 646–674.
doi:10.1016/j.cell.2011.02.013(https://doi.org/10.1016/j.cell.2011.02.013). PMID 21376230 (https://www.ncbi.nlm.ni
h.gov/pubmed/21376230).
6. Cell 100:59 (http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6WSN-4195F
C1-5&_image=fig2&_ba=2&_rdoc=1&_fmt=full&_orig=na&_issn=00928674&_pii=S0092867400816839&view=full&_
acct=C000228598&_version=1&_urlVersion=0&_userid=10&md5=8a5d01ad7c944932873e1fd92e894a25)
7. Hanahan, D; Weinberg, RA (4 March 2011)."Hallmarks of cancer: the next generation".Cell. 144 (5): 646–74.
doi:10.1016/j.cell.2011.02.013(https://doi.org/10.1016/j.cell.2011.02.013). PMID 21376230 (https://www.ncbi.nlm.ni
h.gov/pubmed/21376230).
8. Evan, GI; Vousden, KH (17 May 2001). "Proliferation, cell cycle and apoptosis in cancer".Nature. 411 (6835): 342–8.
doi:10.1038/35077213 (https://doi.org/10.1038/35077213). PMID 11357141 (https://www.ncbi.nlm.nih.gov/pubmed/1
1357141).
9. McClatchey, AI; Yap, AS (October 2012). "Contact inhibition (of proliferation) redux".Current Opinion in Cell Biology.
24 (5): 685–94. doi:10.1016/j.ceb.2012.06.009(https://doi.org/10.1016/j.ceb.2012.06.009). PMID 22835462 (https://
www.ncbi.nlm.nih.gov/pubmed/22835462).
10. Elmore, S (June 2007)."Apoptosis: a review of programmed cell death"(https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC2117903). Toxicologic pathology. 35 (4): 495–516. doi:10.1080/01926230701320337(https://doi.org/10.1080/019
26230701320337). PMC 2117903 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903) . PMID 17562483 (http
s://www.ncbi.nlm.nih.gov/pubmed/17562483).
11. Greenberg, RA (March 2005). "Telomeres, crisis and cancer". Current molecular medicine. 5 (2): 213–8.
doi:10.2174/1566524053586590(https://doi.org/10.2174/1566524053586590). PMID 15974875 (https://www.ncbi.nl
m.nih.gov/pubmed/15974875).
12. http://www.nature.com/nrg/journal/v11/n5/abs/nrg2763.html
13. Bergers, G; Benjamin, LE (June 2003). "Tumorigenesis and the angiogenic switch".Nature Reviews. Cancer. 3 (6):
401–10. doi:10.1038/nrc1093 (https://doi.org/10.1038/nrc1093). PMID 12778130 (https://www.ncbi.nlm.nih.gov/pubm
ed/12778130).
14. van Zijl, F; Krupitza, G; Mikulits, W (2011)."Initial steps of metastasis: cell invasion and endothelial transmigration"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028085). Mutation Research. 728 (1–2): 23–34.
doi:10.1016/j.mrrev.2011.05.002 (https://doi.org/10.1016/j.mrrev.2011.05.002). PMC 4028085 (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC4028085) . PMID 21605699 (https://www.ncbi.nlm.nih.gov/pubmed/21605699).
15. O. Warburg, K. Posener, E. Negelein: "Ueber den Stoffwechsel der Tumoren" Biochemische Zeitschrift, 152, pp.
319–344, 1924. (German). Reprinted in English in the bookOn metabolism of tumorsby O. Warburg, Publisher:
Constable, London, 1930.
16. "Targeting tumour metabolism".Nature Reviews Drug Discovery. 9 (7): 503–504. 2010. doi:10.1038/nrd3215 (https://
doi.org/10.1038/nrd3215). ISSN 1474-1776 (https://www.worldcat.org/issn/1474-1776). PMID 20592733 (https://ww
w.ncbi.nlm.nih.gov/pubmed/20592733).
17. Forrest MD. "Why cancer cells have a more hyperpolarised mitochondrial membrane potential and emergent
prospects for therapy".bioRxiv 025197 (https://doi.org/10.1101/025197) .
18. Gottlieb E, Armour SM, Harris MH, Thompson CB (2003)."Mitochondrial membrane potential regulates matrix
configuration and cytochrome c release during apoptosis"(http://www.nature.com/cdd/journal/v10/n6/full/4401231a.h
tml). Cell Death Differ. 10: 709–717. doi:10.1038/sj.cdd.4401231(https://doi.org/10.1038/sj.cdd.4401231).
19. Barañano KW, Hartman AL (2008). "The ketogenic diet: uses in epilepsy and other neurologic illnesses"(https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC2898565). Curr Treat Options Neurol. 10 (6): 410–9. doi:10.1007/s11940-008-
0043-8 (https://doi.org/10.1007/s11940-008-0043-8). PMC 2898565 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
2898565) . PMID 18990309 (https://www.ncbi.nlm.nih.gov/pubmed/18990309).
20. Allen BG, Bhatia SK, Anderson CM, et al. (Oct 2011). "Ketogenic diets as an adjuvant cancer therapy: History and
potential mechanism".Redox Biol. 2C: 327–337. doi:10.1016/j.eplepsyres.2011.09.022(https://doi.org/10.1016/j.epl
epsyres.2011.09.022). PMID 22019313 (https://www.ncbi.nlm.nih.gov/pubmed/22019313).
21. Scheck AC, Abdelwahab MG, Fenton KE, Staf ford P (October 2011). "The ketogenic diet for the treatment of glioma:
insights from genetic profiling".Epilepsy Res. 100 (3): 327–37. doi:10.1016/j.eplepsyres.2011.09.022(https://doi.org/
10.1016/j.eplepsyres.2011.09.022). PMID 22019313 (https://www.ncbi.nlm.nih.gov/pubmed/22019313).
22. "HeLa nuclear extract lysate (ab14655)"(http://www.abcam.com/hela-nuclear-extract-lysate-ab14655.html). abcam.
23. Lazebnik Y (April 2010). "What are the hallmarks of cancer?".Nat. Rev. Cancer. 10 (4): 232–3. doi:10.1038/nrc2827
(https://doi.org/10.1038/nrc2827). PMID 20355252 (https://www.ncbi.nlm.nih.gov/pubmed/20355252).
24. Sonnenschein C, Soto AM (Sep 2013)."The aging of the 2000 and 2011 Hallmarks of Cancer reviews: A critique" (ht
tp://www.ias.ac.in/jbiosci/sep2013/651.pdf)(PDF). J. Biosci. 38 (3): 651–63. doi:10.1007/s12038-013-9335-6(https://
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PMID 23938395 (https://www.ncbi.nlm.nih.gov/pubmed/23938395).

Bibliography
Hanahan D, Weinberg RA (January 2000). "The hallmarks of cancer".Cell. 100 (1): 57–70. doi:10.1016/S0092-
8674(00)81683-9. PMID 10647931..
Hanahan D, Weinberg RA (March 2011). "Hallmarks of cancer: the next generation".Cell. 144 (5): 646–74.
doi:10.1016/j.cell.2011.02.013. PMID 21376230..

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